Compounds and compositions for the treatment of ocular disorders

ABSTRACT

The disclosure describes prodrugs and derivatives of prostaglandins, carbonic anhydrase inhibitors, kinase inhibitors, beta-adrenergic receptor antagonists and other drugs, as well as controlled delivery formulations containing such prodrugs and derivatives, for the treatment of ocular disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 15/273,686, filed Sep. 22, 2016, which claims the benefit ofprovisional U.S. Application No. 62/222,095, filed Sep. 22, 2015. Theentirety of these applications are hereby incorporated by reference forall purposes.

BACKGROUND

The eye is a complex organ with unique anatomy and physiology. Thestructure of the eye can be divided into two parts, the anterior andposterior. The cornea, conjunctiva, aqueous humor, iris, ciliary bodyand lens are in the anterior portion. The posterior portion includes thesclera, choroid, retinal pigment epithelium, neural retina, optic nerveand vitreous humor. The most important diseases affecting the anteriorsegment include glaucoma, allergic conjunctivitis, anterior uveitis andcataracts. The most prevalent diseases affecting the posterior segmentof the eye are dry and wet age-related macular degeneration (AMD) anddiabetic retinopathy.

Typical routes of drug delivery to the eye are topical, systemic,subconjunctival, intravitreal, puntal, intrasceral, transscleral,anterior or posterior sub-Tenon's, suprachoroidal, choroidal,subchoroidal, and subretinal.

To address issues of ocular delivery, a large number of types ofdelivery systems have been devised. Such include conventional (solution,suspension, emulsion, ointment, inserts and gels); vesicular (liposomes,exosomes, niosomes, discomes and pharmacosomes), advanced materials(scleral plugs, gene delivery, siRNA and stem cells); and controlledrelease systems (implants, hydrogels, dendrimers, iontophoresis,collagen shields, polymeric solutions, therapeutic contact lenses,cyclodextrin carriers, microneedles and microemulsions and particulates(microparticles and nanoparticles)).

Topical drops are the most widely used non-invasive routes of drugadministration to treat anterior ocular diseases. However, a number ofbarriers exist to effective topical delivery, including tear turnover,nasolacrimal drainage, reflex blinking, and the barrier of the mucosalmembrane. It is considered that less than 5% of topically applieddosages reach the deeper ocular tissue.

The patient may be required to instill topical drops up to four times aday. Indeed, certain patients, including corneal transplant recipients,require therapeutic doses of medications to be continuously maintainedin the corneal tissues and some patients are required to endure lengthyand arduous dosing regimens that often involve up to hourly application.Each repeat dosing not only requires a further investment of a patient'stime, but also increases the chance of irritation and non-compliance.

Drug delivery to the posterior area of the eye usually requires adifferent mode of administration from topical drops, and is typicallyachieved via an intravitreal injection, periocular injection or systemicadministration. Systemic administration is not preferred given the ratioof volume of the eye to the entire body and thus unnecessary potentialsystemic toxicity. Therefore, intravitreal injections are currently themost common form of drug administration for posterior disorders.However, intravitreal injections also risk problems due to the commonside effect of inflammation to the eye caused by administration offoreign material to this sensitive area, endophthalmitis, hemorrhage,retinal detachment and poor patient compliance.

Transscleral delivery with periocular administration is seen as analternative to intravitreal injections, however, ocular barriers such asthe sclera, choroid, retinal pigment epithelium, lymphatic flow andgeneral blood flow compromise efficacy.

To treat ocular diseases, and in particular disease of the posteriorchamber, the drug must be delivered in an amount and for a duration toachieve efficacy. This seemingly straightforward goal is difficult toachieve in practice.

Examples of common drug classes used for ocular disorders include:prostaglandins, carbonic anhydrase inhibitors, receptor tyrosine kinaseinhibitors (RTKIs), beta-blockers, alpha-adrenergic agonists,parasympathomimetics, epinephrine, and hyperosmotic agents.

Although a number of prostaglandin carboxylic acids are effective intreating eye disorders, for example, lowering intraocular pressure(IOP), their hydrophilic nature can lead to rapid clearance from thesurface of the eye before effective therapy can be achieved. As aresult, prostaglandins are dosed in the form of selected esters to allowentry to the eye and a “prolonged” residence. When in the eye, nativeesterase enzymes cleave the prostaglandin ester to release the activespecies. Despite this innovation, current drop administeredprostaglandins, for example, latanoprost, bimatoprost, and travoprost,still require daily or several times daily dosing regimens and may causeirritation or hyperemia to the eye in some patients. In addition, nearlyhalf of patients on prostaglandin therapy for glaucoma require a secondagent for control of IOP (Physician Drug and Diagnosis Audit (PDDA) fromVerispan, L.L.C. January-June, 2003)

Carbonic anhydrase inhibitors (CAIs) are used as an alternative andsometimes in conjunction with prostaglandins to treat eye disorders.Unfortunately, compliancy issues can occur as these medications alsorequire daily or dosing up to four times a day, and may also causeirritation or hyperemia to the eye in some patients.

Another potential avenue for the treatment of ocular disorders involvesprotecting neurons directly. Preliminary data on receptor tyrosinekinase inhibitors (RTKIs) and dual leucine zipper kinase inhibitors(DLKIs) suggests that instead of treating increasing ocular pressure,molecules such as Sunitinib and Crizotinib can prevent the nerve damagethat is associated with it. Unfortunately, Sunitinib has had observedhepatotoxicity in both clinical trials and post-marketing clinical use.

References that describe treatments of ocular disorders and thesynthesis of compounds related to treating ocular disorders include thefollowing: Ongini et al., U.S. Pat. No. 8,058,467 titled “Prostaglandinderivatives”; Qlt Plug Delivery Inc, WO2009/035565 titled “Prostaglandinanalogues for implant devices and methods”; Allergan Inc, U.S. Pat. No.5,446,041 titled “Intraocular pressure reducing 11-acyl prostaglandins”;Upjohn Co., DE2263393 titled “9-O-Acylated prostaglandins F2a”; Shionogi& Co. patent publication 948,179 titled “Treatment for hypertension orglaucoma in eyes”; Ragactive, EP1329453 titled “Method for obtaining4-(n-alkylamine)-5,6-dihydro-4h-thieno-(2,3-b)-thiopyran-2-sulfonamide-7, 7-dioxides andintermediate products”; and American Cyanamid Co. GB844946 titled“2-(N-Substituted)acylamino-1,3,4-thiadiazole-5-sulfonamides”.

Other publications include Vallikivi, I., et al. (2005). “The modellingand kinetic investigation of the lipase-catalyzed acetylation ofstereoisomeric prostaglandins.” J. Mol. Catal. B: Enzym. 35(1-3): 62-69;Parve, O., et al. (1999). “Lipase-catalyzed acylation of prostanoids.”Bioorg. Med. Chem. Lett. 9(13): 1853-1858; and Carmely, S., et al.(1980). and “New prostaglandin (PGF) derivatives from the soft coralLobophyton depressum.” Tetrahedron Lett. 21(9): 875-878.

Patent applications that describe DLK inhibitors include: Zhejiang DTRMBiopharma Co., patent publication WO2014146486 titled “Three-levelcyclic amine ALK kinase inhibitor for treating cancer”; Kyowa HakkoKogyo Co., patent publication WO2005012257 titled “IndazoleDerivatives”; Genetech, patent publication WO2014177524 titled “C-linkedheterocycloalkyl substituted pyrimidines and their uses”, and patentpublication WO2013174780 titled “Substituted dipyridylamines and usesthereof”.

Patent applications that describe derivatives of prostaglandins include:Allergan, U.S. Pat. No. 5,767,154 titled “5-tran-prostaglandins of the Fseries and their use as ocular hypotensives”, U.S. Pat. No. 5,767,154titled “5-trans-prostaglandins of the F series and their use as ocularhypotensives”; Alcon Laboratories, EP0667160A2 titled “Use of certainprostaglandin analogues to treat glaucoma and ocular hypertension”,EP667160 titled “Use of certain prostaglandin analogues to treatglaucoma and ocular hypertension; Asahi glass company and SantenPharmaceutical Co., EP0850926A2 titled “Difluoroprostaglandinderivatives and their use”; Asahi Glass Co., JP2000080075 titled“Preparation of 15-deoxy-15,15-difluoroprostaglandins as selective andchemically-stable drugs”, JP11255740 titled “Preparation of15-deoxy-15-monofluoroprostaglandin derivatives”, JP10087607 titled“Preparation of fluorine-containing prostaglandins as agents forinducing labor and controlling animal sexual cycle”, WO9812175 titled“Preparation of fluorinated prostaglandin derivatives for treatment ofglaucoma”; Santen Pharmaceutical Co., JP10259179 titled “Preparation ofmulti-substituted aryloxy-group containing prostaglandins and theiruse”, EP850926 titled “Preparation of difluoroprostaglandin derivativesand their use for treatment of an eye disease”;

The object of this invention is to provide improved compounds,compositions and methods to treat ocular disorders.

SUMMARY

The present invention includes new compounds and compositions, includingcontrolled release compositions, with improved properties for oculartherapy. In one embodiment, the invention is an improved method fordelivering an active drug to the eye that includes presenting the drug,which achieves a controlled release of the active material, includingwhen administered in a sustained delivery system such as a polymericcomposition, a hydrophobic liquid, a hydrophobic solid, or a form ofslow release reservoir or encapsulation. Often, ocular therapies aredelivered to the eye in a form that is hydrophilic to be soluble inocular fluid. In this invention, a highly hydrophobic prodrug orderivative of an active compound which can be delivered in a polymericcontrolled delivery system is provided wherein the hydrophobic compoundis more soluble within polymeric material than the ocular fluid, whichslows release into ocular aqueous fluid.

Commercial prostaglandins are generally provided as lower alkyl chainesters (e.g., up to pivaloyl). Also see for example, WO2009/035565titled “Prostaglandin analogues for implant devices and methods” whichdisclosed the presentation of a prostaglandin with a long chain alkylester, however, the presently disclosed prostaglandin derivativesrepresent improvements over these compounds with either increasedmasking of hydroxyl groups remaining on the molecule or alternativehydrophobic prodrug moieties that can provide enhanced performance.

In another embodiment, the compounds provided herein are designed todeliver two active compounds with different, but additive or synergisticmechanisms of action for ocular therapy to the eye. This represents acontribution to the art over simple combination therapy, including forglaucoma, wherein multiple eye drops or a mixture of multiple eye dropsare delivered.

In certain embodiments of the invention, at least one of the activetherapeutic agents delivered in modified form is selected from a kinaseinhibitor (for example, a tyrosine kinase inhibitor or a dual leucinezipper kinase inhibitor), a prostaglandin or a carbonic anhydraseinhibitor. Non-limiting examples of active therapeutic agents includeSunitinib or a derivatized version of Sunitinib (for example, with ahydroxyl, amino, thio, carboxy, keto or other functional group insteadof fluoro that can be used to covalently connect the hydrophobicmoiety), Latanoprost, Dinoprost, Travoprost, Tafluprost, Unoprostone,Timolol, Brinzolamide, Dorzolamide, Acetazolamide, Methazolamide,Crizotinib, KW-2449, and Tozasertib.

One achievement of the invention is to provide for the controlledadministration of active compounds to the eye, over a period of at leasttwo, three, four, five or six months or more in a manner that maintainsat least a concentration in the eye that is effective for the disorderto be treated. In one embodiment, the drug is administered in apolymeric formulation that provides a controlled release that is linear.In another embodiment, the release is not linear; however, even thelowest concentration of release over the designated time period is at orabove a therapeutically effective dose. In one embodiment, this isachieved by formulating a hydrophobic prodrug of the invention in apolymeric delivery material such as a polymer or copolymer that includesat least lactic acid, glycolic acid, propylene oxide or ethylene oxide.In a particular embodiment, the polymeric delivery system includespolylactide-co-glycolide with or without polyethylene glycol. Forexample, the hydrophobic drug may be delivered in a mixture of PLGA andPLGA-PEG or PEG. In another embodiment, the polymer includes apolyethylene oxide (PEO) or polypropylene oxide (PPO). In certainaspects, the polymer can be a random, diblock, triblock or multiblockcopolymer (for eample example, a polylactide, apolylactide-co-glycolide, polyglycolide or Pluronic). For injection intothe eye, the polymer is pharmaceutically acceptable and typicallybiodegradable so that it does not have to be removed.

The decreased rate of release of the active material to the ocularcompartment may result in decreased inflammation, which has been asignificant side effect of ocular therapy to date.

It is also important that the decreased rate of release of the drugwhile maintaining efficacy over an extended time of up to 4, 5 or 6months be achieved using a particle that is small enough foradministration through a needle without causing significant damage ordiscomfort to the eye and not to give the illusion to the patient ofblack spots floating in the eye. This typically means the controlledrelease particle should be less than approximately 300, 250, 200, 150,100, 50, 45, 40, 35, or 30 jam, such as less than approximately 29, 28,27, 26, 25, 24, 23, 22 21, or 20 am. In one aspect, the particles do notagglomerate in vivo to form larger particles, but instead in generalmaintain their administered size and decrease in size over time.

The hydrophobicity of the conjugated drug can be measured using apartition coefficient (P; such as Log P in octanol/water), ordistribution coefficient (D; such as Log D in octanol/water) accordingto methods well known to those of skill in the art. Log P is typicallyused for compounds that are substantially un-ionized in water and Log Dis typically used to evaluate compounds that ionize in water. In certainembodiments, the conjugated derivatized drug has a Log P or Log D ofgreater than approximately 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6. In otherembodiments, the conjugated derivatized drug has a Log P or Log D whichis at least approximately 1, 1.5, 2, 2.5, 3, 3.5 or 4 Log P or Log Dunits, respectively, higher than the parent hydrophilic drug.

This invention includes an active compound of Formula I, Formula II,Formula II′, Formula III, Formula IV, Formula V, Formula VI, FormulaVII, Formula VII′, Formula VIII, Formula IX, Formula X, Formula XI,Formula XII, Formula XIV, Formula XV, Formula XVI, Formula XVII, FormulaXVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, FormulaXXIII, or a pharmaceutically acceptable salt or composition thereof. Inone embodiment, an active compound or its salt or composition, asdescribed herein, is used to treat a medical disorder which is glaucoma,a disorder mediated by carbonic anhydrase, a disorder or abnormalityrelated to an increase in intraocular pressure (IOP), a disordermediated by nitric oxide synthase (NOS), or a disorder requiringneuroprotection such as to regenerate/repair optic nerves. In anotherembodiment more generally, the disorder treated is allergicconjunctivitis, anterior uveitis, cataracts, dry or wet age-relatedmacular degeneration (AMD) or diabetic retinopathy.

Compounds of Formula I and Formula II are prodrugs or derivatives ofprostaglandins.

In one embodiment compounds of Formula I and Formula II are hydrophobicprodrugs of prostaglandins.

Compounds of Formula III, Formula IV, Formula V, and Formula VI areprodrugs of the carbonic anhydrase inhibitors Brinzolamide, Dorzolamide,Acetazolamide, and Methazolamide respectively.

Compounds of Formula VII are single agent prodrug conjugates of aprostaglandin and a carbonic anhydrase inhibitor allowing release ofboth compounds in the eye. In one embodiment both compounds are releasedconcurrently.

In one embodiment compounds of Formula VIII are single agent prodrugconjugates of a prostaglandin and a Sunitinib derivative allowingrelease of both compounds in the eye. In one embodiment both compoundsare released concurrently.

In an alternative embodiment compounds of Formula VIII are single agentprodrug conjugates of a carbonic anhydrase inhibitor and a Sunitinibderivative allowing release of both compounds in the eye. In oneembodiment both compounds are released concurrently.

Compounds of Formula IX, Formula X, Formula XI, and Formula XII areprodrugs of the dual leucine zipper kinase inhibitors Crizotinib,KW2449, piperidino analogs, and a Tozasertib derivative respectively.

Compounds of Formula XIV are prodrugs or derivatives of Sunitinibanalgoues (Sunitinib with a heteroatom or carboxy instead of a fluorogroup).

In one embodiment compounds of Formula XIV are hydrophobic prodrugs ofSunitinib derivatives.

Compounds of Formula XV are single agent prodrug conjugates of aSunitinib derivative and a carbonic anhydrase inhibitor allowing releaseof both compounds in the eye. In one embodiment both compounds arereleased concurrently.

Compounds of Formula XVI are prodrugs or derivatives of Timolol.

In one embodiment compounds of Formula XVI are hydrophobic prodrugs ofTimolol.

In one embodiment compounds of Formula XVII are single agent prodrugconjugates of Timolol and a carbonic anhydrase inhibitor allowingrelease of both compounds in the eye. In one embodiment both compoundsare released concurrently.

In an alternative embodiment compounds of Formula XVII are single agentprodrug conjugates of Timolol and a prostaglandin allowing release ofboth compounds in the eye. In one embodiment both compounds are releasedconcurrently.

These compounds can be used to treat ocular disorders in a host in needthereof, typically a human. In one embodiment, a method for thetreatment of such a disorder is provided that includes theadministration of an effective amount of a compound of Formula I,Formula II, Formula II′, Formula III, Formula IV, Formula V, Formula VI,Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII, FormulaVII′, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIII ora pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier, including a polymeric carrier, asdescribed in more detail below.

Another embodiment is provided that includes the administration of aneffective amount of an active compound or a pharmaceutically acceptablesalt thereof, optionally in a pharmaceutically acceptable carrier,including a polymeric carrier, to a host to treat an ocular or otherdisorder that can benefit from topical or local delivery. The therapycan be delivery to the anterior or posterior chamber of the eye. Inspecific aspects, the active compound is administered to treat adisorder of the cornea, conjunctiva, aqueous humor, iris, ciliary body,lens sclera, choroid, retinal pigment epithelium, neural retina, opticnerve or vitreous humor.

Any of the compounds described herein (Formula I, Formula II, FormulaII′, Formula III, Formula IV, Formula V, Formula VI, Formula III′,Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIV,Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,Formula XX, Formula XXI, Formula XXII, or Formula XXIII) can beadministered to the eye in a composition as described further herein inany desired form of administration, including via intravitreal,intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar,peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival,subconjunctival, episcleral, posterior juxtascleral, circumcorneal, andtear duct injections, or through a mucus, mucin, or a mucosal barrier,in an immediate or controlled release fashion.

In certain embodiments, the conjugated active drug is delivered in abiodegradable microparticle or nanoparticle that has at leastapproximately 5, 7.5, 10, 12.5, 15, 20, 25 or 30% by weight conjugatedactive drug. In some embodiments, the biodegradable microparticledegrades over a period of time of at least approximately 3 months, 4months, 5 months or 6 months or more. In some embodiments, the loadedmicroparticles are administered via subconjunctival or subchoroidalinjection.

In all of the polymer moieties described in this specification, wherethe structures are depicted as block copolymers (for example, blocks of“x” followed by blocks of “y”), it is intended that the polymer can be arandom or alternating copolymer (for example, “x” and “y” are eitherrandomly distributed or alternate).

Non-limiting examples of Formula I and Formula II include at leasthydrophobic prodrugs or derivatives of the following prostaglandins:

Non-limiting examples of Formula III, Formula IV, Formula V, and FormulaVI are prodrugs of Brinzolamide, Dorzolamide, Acetazolamide, andMethazolamide respectively.

The disclosure provides a prostaglandin prodrug of Formula I:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

L¹ is selected from:

L² is selected from:

A is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy,and alkyloxy wherein each group can be optionally substituted withanother desired substituent group which is pharmaceutically acceptableand sufficiently stable under the conditions of use, for exampleselected from R⁵.

Non-limiting examples of Formula I include:

R¹, R², and R³ are selected from: —C(O)R⁴, C(O)A, and hydrogen whereineither R¹ or R² cannot be hydrogen and wherein R¹, R², and R³ can befurther optionally substituted with R⁵.

R⁴ is selected from:

-   -   (i) —C₁₀-C₃₀alkylR⁵, —C₁₀-C₃₀alkenylR⁵, —C₁₀-C₃₀alkynylR⁵,        —C₁₀-C₃₀alkenylalkynylR⁵, —C₁₀-C₃₀alkyl, —C₁₀-C₃₀alkenyl,        —C₁₀-C₃₀alkynyl, —C₁₀-C₃₀alkenylalkynyl;    -   (ii) an unsaturated fatty acid residue including but not limited        to the carbon chains from linoleic acid        (—(CH₂)₈(CH)₂CH₂(CH)₂(CH₂)₄CH₃)), docosahexaenoic acid        (—(CH₂)₃(CHCHCH₂)₆CH₃)), eicosapentaenoic acid        (—(CH₂)₄(CHCHCH₂)₅CH₃)), alpha-linolenic acid        (—(CH₂)₈(CHCHCH₂)₃CH₃)), stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid and mead acid, and wherein, if        desired, each of which can be substituted with R⁵.

Non-limiting examples of R⁴ include:

wherein n, m, and o can be any integer between 0 and 29 (1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28 or 29) wherein n+m+o is 7 to 30 carbons and wherein x andy can be any integer between 1 and 30 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29 or 30). In one embodiment x and y are independently selected from thefollowing ranges: 1 to 5, 6 to 11, 12 to 17, 18 to 23, and 24 to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30).

In one embodiment, —C₁₀-C₃₀ as used in the definition of R⁴ is —C₁₀-C₂₈,—C₁₀-C₂₆, —C₁₀-C₂₄, —C₁₀-C₂₂, —C₁₀-C₂₀, —C₁₀-C₁₈, —C₁₀-C₁₆, —C₁₀-C₁₄, or—C₁₀-C₁₂.

R⁵ is selected from: halogen, hydroxyl, cyano, mercapto, amino, alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy,—S(O)₂alkyl, —S(O)alkyl, —P(O)(Oalkyl)₂, B(OH)₂, —Si(CH₃)₃, —COOH,—COOalkyl, and —CONH₂, each of which except halogen, cyano, and—Si(CH₃)₃ may be optionally substituted, for example with halogen,alkyl, aryl, heterocycle or heteroaryl if desired and if the resultingcompound achieves the desired purpose, wherein the group cannot besubstituted with itself, for example alkyl would not be substituted withalkyl.

While various structures are depicted as block copolymers (i.e, blocksof “x” followed by blocks of “y”) in some embodiments, the polymer canbe a random or alternating copolymer (“x” and “y” are either randomlydistributed or alternate).

The disclosure also provides a compound of Formula II:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

Non-limiting examples of Formula II include:

R⁶ is selected from:

-   -   (i) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid)        including:

or polyglycolic acid, or a polyester, polyamide, or other biodegradablepolymer, each of which can be capped to complete the terminal valence.In some embodiments, the compound can be capped with hydrogen, or can becapped to create a terminal ester or ether. For example, the moiety canbe capped with a terminal hydroxyl or carboxy which can be furtherderivatized to an ether or ester;

-   -   (ii) —C₁₀-C₃₀alkylR⁵, —C₁₀-C₃₀alkenylR⁵, —C₁₀-C₃₀alkynylR⁵,        —C₁₀-C₃₀alkenylalkynylR⁵, —C₁₀-C₃₀alkyl, —C₁₀-C₃₀alkenyl,        —C₁₀-C₃₀alkynyl, —C₁₀-C₃₀alkenylalkynyl;    -   (iii) an unsaturated fatty acid residue including but not        limited the carbon fragment taken from linoleic acid        (—(CH₂)₈(CH)₂CH₂(CH)₂(CH₂)₄CH₃)), docosahexaenoic acid        (—(CH₂)₃(CHCHCH₂)₆CH₃)), eicosapentaenoic acid        (—(CH₂)₄(CHCHCH₂)₅CH₃)), alpha-linolenic acid        (—(CH₂)₈(CHCHCH₂)₃CH₃)) stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid or mead acid;    -   (iv) alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,        heterocycloalkyl, arylalkyl, heteroarylalkyl;

wherein R⁶ can only be selected from (ii), (iii), and (iv) above if atleast one of R⁷ and R⁸, is selected to be R⁵⁰.

In one embodiment, —C₁₀-C₃₀ as used in the definition of R⁶ is —C₁₀-C₂₈,—C₁₀-C₂₆, —C₁₀-C₂₄, —C₁₀-C₂₂, —C₁₀-C₂₀, —C₁₀-C₁₈, —C₁₀-C₁₆, —C₁₀-C₁₄, or—C₁₀-C₁₂.

R⁷ and R⁸, are independently selected from: —C(O)R⁴, —C(O)A, hydrogen,and R⁵⁰.

R⁵⁰ is selected from carbonyl derivatives of polyethylene glycol,polypropylene glycol, polypropylene oxide, polylactic acid, andpoly(lactic-co-glycolic acid) including:

or polyglycolic acid, or a polyester, polyamide, or other biodegradablepolymer, each of which can be capped to complete the terminal valence.In some embodiments, the compound can be capped with hydrogen, or can becapped to create a terminal ester or ether. For example, the moiety canbe capped with a terminal hydroxyl or carboxy which can be furtherderivatized to an ether or ester.

Non-limiting examples of R⁵⁰ include:

wherein x and y are as defined above.

Additional non-limiting examples of R⁵⁰ include:

wherein x and y are as defined above.

In one embodiment R⁶ is isopropyl.

In one embodiment a compound of Formula I or Formula II is hydrolysableby an enzyme in vivo, such as an esterase.

In another embodiment a compound of Formula I or Formula II or acomposition thereof is for use in the cosmetic enhancement of eyelashhair or eyebrow hair.

In another embodiment a compound of Formula I or Formula II or acomposition thereof is used for the growth of eyelash or eyebrow hair.

The disclosure also provides a compound of Formula II′:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

L³ is selected from:

Non-limiting examples of Formula II′ include:

R⁴¹ is selected from:

-   -   (i) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid),

polyglycolic acid, a polyester, a polyamide, or other biodegradablepolymer, wherein in some embodiments a terminal hydroxy or carboxy groupcan be substituted to create an ether or ester;

-   -   (ii) —C₁₀-C₃₀alkylR⁵, —C₁₀-C₃₀alkenylR⁵, —C₁₀-C₃₀alkynylR⁵,        —C₁₀-C₃₀alkenylalkynylR⁵, —C₁₀-C₃₀alkyl, —C₁₀-C₃₀alkenyl,        —C₁₀-C₃₀alkynyl, —C₁₀-C₃₀alkenylalkynyl    -   (iii) an unsaturated fatty acid residue including but not        limited the carbon fragment taken from linoleic acid        (—(CH₂)₈(CH)₂CH₂(CH)₂(CH₂)₄CH₃)), docosahexaenoic acid        (—(CH₂)₃(CHCHCH₂)₆CH₃)), eicosapentaenoic acid        (—(CH₂)₄(CHCHCH₂)₅CH₃)), alpha-linolenic acid        (—(CH₂)₈(CHCHCH₂)₃CH₃)) stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid or mead acid;    -   (iv) alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,        heterocycloalkyl, arylalkyl, heteroarylalkyl;

In one embodiment, —C₁₀-C₃₀ as used in the definition of R⁴¹ is—C₁₂-C₂₈, —C₁₂-C₂₆, —C₁₂-C₂₄, —C₁₄-C₂₂, —C₁₄-C₂₀, —C₁₄-C₁₈, —C₁₄-C₁₆, or—C₁₂-C₁₄.

In one embodiment the disclosure provides a prodrug of a carbonicanhydrase inhibitor for ocular therapy, which can be released from atherapeutic, including a polymeric, delivery system while maintainingefficacy over an extended time such as up to 4, 5 or 6 months.

The disclosure also provides prodrugs of Formula III, Formula IV,Formula V and Formula VI:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R¹⁰ is selected from:

-   -   (i) N═C₄-C₃₀alkenylR⁵, —N═C₄-C₃₀alkynylR⁵,        —N═C₄-C₃₀alkenylalkynylR⁵, —N═C₁-C₃₀alkylR⁵, —N═C₄-C₃₀alkenyl,        —N═C₄-C₃₀alkynyl, —N═C₄-C₃₀alkenylalkynyl, —N═C₁-C₃₀alkyl;    -   (ii) an unsaturated fatty acid residue including but not limited        to derivatives of linoleic acid        (—N═CH(CH₂)₇(CH)₂CH₂(CH)₂(CH₂)₄CH₃), docosahexaenoic acid        (—N═CH(CH₂)₂(CHCHCH₂)₆CH₃), eicosapentaenoic acid        (—N═CH(CH₂)₃(CHCHCH₂)₅CH₃), alpha-linolenic acid        (—N═CH(CH₂)₇(CHCHCH₂)₃CH₃), stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid or mead acid, each of which can        be further substituted with R⁵ (including for example a second        R⁵) if valence permits, a stable compound is formed, and the        resulting compound is pharmaceutically acceptable;    -   (iii) polypropylene glycol, polypropylene oxide, polylactic        acid, or poly(lactic-co-glycolic acid) including:

or polyglycolic acid, or a polyester, polyamide, or other biodegradablepolymer, each of which can be capped to complete the terminal valence.In some embodiments, the compound can be capped with hydrogen, or can becapped to create a terminal ester or ether. For example, the moiety canbe capped with a terminal hydroxyl or carboxy which can be furtherderivatized to an ether or ester. And wherein each of which can befurther substituted with R⁵ if valence permits, a stable compound isformed, and the resulting compound is pharmaceutically acceptable; andwherein in some embodiments a terminal hydroxy or carboxy group can besubstituted to create an ether or ester;

-   -   (iv) NH₂ wherein R¹⁵ is R¹⁶;        In an alternative embodiment, R¹⁰ is    -   —NHC(O)C₁₋₂₀alkyl, —NHC(O)C₁₋₂₀alkenyl, —NHC(O)C₁₋₂₀alkynyl,        —NHC(O)(C₁₋₂₀alkyl with at least one R⁵ substituent on the alkyl        chain), —NHC(O)(C₁₋₂₀alkenyl, with at least one R⁵ substituent        on the alkenyl chain) —NHC(O)(C₁₋₂₀alkynyl, with at least one R⁵        substituent on the alkynyl chain), —NH(lactic        acid)₂₋₂₀C(O)C₁₋₂₀alkyl, —NH(lactic acid)₂₋₁₀C(O)C₁₋₂₀alkyl,        —NH(lactic acid)₄₋₂₀C(O)C₁₋₂₀alkyl, —NH(lactic        acid)₂₋₂₀C(O)C₁₋₁₀alkyl, —NH(lactic acid)₂₋₂₀C(O)_(C4-10)alkyl,        —NH(lactic acid)₂₋₂₀C(O)OH, —NH(lactic acid)₂₋₁₀C(O)OH,        —NH(lactic acid)₄₋₂₀C(O)OH, —NH(lactic acid)₂₋₁₀C(O)OH,        —NH(lactic acid)₄₋₁₀C(O)OH,        —NH(lactide-co-glycolide)₂₋₁₀C(O)_(C1-20)alkyl,        —NH(lactide-co-glycolide)₄₋₁₀C(O)_(C1-20)alkyl,        —NH(lactide-co-glycolide)₂₋₁₀C(O)_(C1-10)alkyl,        —NH(lactide-co-glycolide)₂₋₁₀C(O)_(C4-20)alkyl, —NH(glycolic        acid)₂₋₁₀C(O)_(C1-10)alkyl, —NH(glycolic        acid)₄₋₁₀C(O)_(C1-10)alkyl, —NH(lactic        acid)₄₋₁₀C(O)_(C1-10)alkyl, —NH(lactic        acid)₂₋₁₀C(O)_(C1-10)alkyl, NH(lactic        acid)₂₋₁₀C(O)_(C4-10)alkyl, —NH(lactic        acid)₂₋₁₀C(O)_(C4-10)alkyl, or —NH(lactic        acid)₂₋₁₀C(O)_(C4-10)alkyl.

R¹⁵ is selected from R¹⁶ and R¹⁷.

R¹⁶ is selected from:

-   -   (i) —C(O)C₃-C₃₀alkylR⁵, —C(O)C₃-C₃₀alkenylR⁵,        —C(O)C₃-C₃₀alkynylR⁵, —C(O)C₃-C₃₀alkenylalkynylR⁵,        —C(O)C₃-C₃₀alkyl, —C(O)C₃-C₃₀alkenyl, —C(O)C₃-C₃₀alkynyl, and        —C(O)C₃-C₃₀alkenylalkynyl;    -   (ii) an unsaturated fatty acid residue including but not limited        the carbonyl fragment taken from linoleic acid        (—C(O)(CH₂)₇(CH)₂CH₂(CH)₂(CH₂)₄CH₃)), docosahexaenoic acid        (—C(O)(CH₂)₂(CHCHCH₂)₆CH₃)), eicosapentaenoic acid        (—C(O)(CH₂)₃(CHCHCH₂)₅CH₃)), alpha-linolenic acid        (—C(O)(CH₂)₇(CHCHCH₂)₃CH₃)) stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid and mead acid;    -   (iii) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid)        including:

or polyglycolic acid, or a polyester, polyamide, or other biodegradablepolymer, each of which can be capped to complete the terminal valence.In some embodiments, the compound can be capped with hydrogen, or can becapped to create a terminal ester or ether. For example, the moiety canbe capped with a terminal hydroxyl or carboxy which can be furtherderivatized to an ether or ester.

R¹⁷ is selected from: H and —C(O)A.

In one embodiment, —C₃-C₃₀ as used in the definition of R¹⁰ is —C₃-C₂₈,—C₃-C₂₆, —C₃-C₂₄, —C₃-C₂₂, —C₃-C₂₀, —C₃-C₁₈, —C₃-C₁₆, —C₃-C₁₄, —C₃-C₁₂,—C₅-C₁₂, —C₇-C₁₂, or —C₇-C₁₀.

In one embodiment R¹⁰ is selected from:

-   -   (i) —N═CH—C₃-C₃₀alkenylR⁵, —N═CH—C₃-C₃₀alkynylR⁵,        —N═CH—C₃-C₃₀alkenylalkynylR⁵, —N═C₁-C₃₀alkylR⁵,        —N═CH—C₃-C₃₀alkenyl, —N═CH—C₃-C₃₀alkynyl,        —N═CH—C₃-C₃₀alkenylalkynyl, —N═C₁-C₃₀alkyl;

Non-limiting examples of R¹⁰ include:

wherein n, m, o, x and y are as defined above.

The disclosure also provides prodrugs of Formula III′, Formula IV′,Formula V′ and Formula VI′:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R⁴² is selected from:

-   -   (i) —N═CH—C₃-C₃₀alkenylR⁵, —N═CH—C₃-C₃₀alkynylR⁵,        —N═CH—C₃-C₃₀alkenylalkynylR⁵, —N═C₁-C₃₀alkylR⁵,        —N═CH—C₃-C₃₀alkenyl, —N═CH—C₃-C₃₀alkynyl,        —N═CH—C₃-C₃₀alkenylalkynyl, —N═C₁-C₃₀alkyl, —NHC₃-C₃₀alkenylR⁵,        —NH—C₃-C₃₀alkynylR⁵, —NH—C₅-C₃₀alkenylalkynylR⁵,        —NHC₀-C₃₀alkylR⁵, —NHC₃-C₃₀alkenylR¹⁶, —NH—C₃-C₃₀alkynylR¹⁶,        —NH—C₅-C₃₀alkenylalkynylR¹⁶, —NHC₀-C₃₀alkylR¹⁶,    -   (ii) An imine, amine or amide linked unsaturated fatty acid        residue including but not limited to derivatives of linoleic        acid        (—N═CH(CH₂)₇(CH)₂CH₂(CH)₂(CH₂)₄CH₃—NHCH₂(CH₂)₇(CH)₂CH₂(CH)₂(CH₂)₄CH₃,        or NHC(O)(CH₂)₇(CH)₂CH₂(CH)₂(CH₂)₄CH₃), docosahexaenoic acid        (—N═CH(CH₂)₂(CHCHCH₂)₆CH₃—NH(CH₂)₃(CHCHCH₂)₆CH₃,        NHC(O)(CH₂)₂(CHCHCH₂)₆CH₃), eicosapentaenoic acid        (—N═CH(CH₂)₃(CHCHCH₂)₅CH₃, —NH(CH₂)₄(CHCHCH₂)₅CH₃, or        NHC(O)(CH₂)₃(CHCHCH₂)₅CH₃), alpha-linolenic acid        (—N═CH(CH₂)₇(CHCHCH₂)₃CH₃, —NH(CH₂)₄(CHCHCH₂)₅CH₃, or        NHC(O)(CH₂)₃(CHCHCH₂)₅CH₃), stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid or mead acid, each of which can        be further substituted with R⁵ (including for example a second        R⁵) if valence permits, a stable compound is formed, and the        resulting compound is pharmaceutically acceptable;    -   (iii) An imine, amine or amide linked polypropylene glycol, an        imine, amine or amide linked polypropylene oxide, an imine,        amine or amide linked polylactic acid, or an imine, amine or        amide linked poly(lactic-co-glycolic acid),

an imine, amine or amide linked polyglycolic acid, a polyester, apolyamide, or other biodegradable polymer, each of which can be furthersubstituted with R⁵ if valence permits, a stable compound is formed, andthe resulting compound is pharmaceutically acceptable; and wherein insome embodiments a terminal hydroxy or carboxy group can be substitutedto create an ether or ester, respectively;

-   -   (iv) —NHC(O)C₁₋₂₀alkyl, —NHC(O)C₁₋₂₀alkenyl,        —NHC(O)C₁₋₂₀alkynyl, —NHC(O)(C₁₋₂₀alkyl with at least one R⁵        substituent on the alkyl chain), —NHC(O)(C₁₋₂₀alkenyl, with at        least one R⁵ substituent on the alkenyl chain)        —NHC(O)(C₁₋₂₀alkynyl, with at least one R⁵ substituent on the        alkynyl chain), —NH(lactic acid)₂₋₂₀C(O)C₁₋₂₀alkyl, —NH(lactic        acid)₂₋₁₀C(O)C₁₋₂₀alkyl, —NH(lactic acid)₄₋₂₀C(O)C₁₋₂₀alkyl,        —NH(lactic acid)₂₋₂₀C(O)C₁₋₁₀alkyl, —NH(lactic        acid)₂₋₂₀C(O)_(C4-10)alkyl, —NH(lactic acid)₂₋₂₀C(O)OH,        —NH(lactic acid)₂₋₁₀C(O)OH, —NH(lactic acid)₄₋₂₀C(O)OH,        —NH(lactic acid)₂₋₁₀C(O)OH, —NH(lactic acid)₄₋₁₀C(O)OH,        —NH(lactide-co-glycolide)₂₋₁₀C(O)_(C1-20)alkyl,        —NH(lactide-co-glycolide)₄₋₁₀C(O)_(C1-20)alkyl,        —NH(lactide-co-glycolide)₂₋₁₀C(O)_(C1-10)alkyl,        —NH(lactide-co-glycolide)₂₋₁₀C(O)_(C4-20)alkyl, —NH(glycolic        acid)₂₋₁₀C(O)_(C1-10)alkyl, —NH(glycolic        acid)₄₋₁₀C(O)_(C1-10)alkyl, —NH(lactic        acid)₄₋₁₀C(O)_(C1-10)alkyl, —NH(lactic        acid)₂₋₁₀C(O)_(C1-10)alkyl, NH(lactic        acid)₂₋₁₀C(O)_(C4-10)alkyl, —NH(lactic        acid)₂₋₁₀C(O)_(C4-10)alkyl, or —NH(lactic        acid)₂₋₁₀C(O)_(C4-10)alkyl

wherein R⁵, R¹⁵, x, and y are as defined above.

In one embodiment, —C₃-C₃₀ as used in the definition of R⁴² is —C₃-C₂₈,—C₃-C₂₆, —C₃-C₂₄, —C₃-C₂₂, —C₃-C₂₀, —C₃-C₁₈, —C₃-C₁₆, —C₃-C₁₄, —C₃-C₁₂,—C₅-C₁₂, —C₇-C₁₂, or —C₇-C₁₀.

Additional non-limiting examples of R¹⁶ include:

The disclosure also provides a prodrug of Formula VII:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R¹¹ is selected from:

-   -   (i) R¹²;    -   (ii) —NH—C₄-C₃₀alkenyl-C(O)R¹², —NH—C₄-C₃₀alkynyl-C(O)R¹²,        —NH—C₄-C₃₀alkenylalkynyl-C(O)R¹², —NH—C₂-C₃₀alkyl-C(O)R¹²,        —O—C₄-C₃₀alkenyl-C(O)R¹², —O—C₄-C₃₀alkynyl-C(O)R¹²,        —O—C₄-C₃₀alkenylalkynyl-C(O)R¹², and —O—C₂-C₃₀alkyl-C(O)R¹²;    -   (iii) —NH—C₄-C₃₀alkenyl=R¹³, —NH—C₄-C₃₀alkynyl=R¹³,        —NH—C₄-C₃₀alkenylalkynyl=R¹³, —NH—C₂-C₃₀alkyl=R¹³,        —O—C₄-C₃₀alkenyl=R¹³, —O—C₄-C₃₀alkynyl=R¹³,        —O—C₄-C₃₀alkenylalkynyl=R¹³, —O—C₂-C₃₀alkyl=R¹³;    -   (iv) functionalized polyethylene glycol, polypropylene glycol,        polypropylene oxide, polylactic acid, and        poly(lactic-co-glycolic acid) including:

-   -   (v) functionalized polyethylene glycol, polypropylene glycol,        polypropylene oxide, polylactic acid, and        poly(lactic-co-glycolic acid) including:

wherein R¹¹ can be further substituted with R⁵ if valence permits, astable compound is formed, and the resulting compound ispharmaceutically acceptable.

In one embodiment R¹¹ is selected from:

—NH—C₄-C₂₉alkenyl-CH═R¹³, —NH—C₄-C₂₉alkynyl-CH═R¹³,—NH—C₄-C₂₉alkenylalkynyl-CH═R¹³, —NH—C₂-C₂₉alkyl-CH═R¹³,—O—C₄-C₂₉alkenyl-CH═R¹³, —O—C₄-C₂₉alkynyl-CH═R¹³,—O—C₄-C₂₉alkenylalkynyl-CH═R¹³, and —O—C₂-C₂₉alkyl-CH═R¹³.

Non-limiting examples of R¹¹ include:

wherein n, m, o, x, and y are as defined above.

R¹² is selected from:

R¹³ is selected from:

In various different embodiments, —C₄-C₂₉ as used in the definition ofR¹¹ may be —C₄-C₂₈, —C₄-C₂₆, —C₄-C₂₄, —C₆-C₂₂, —C₆-C₂₀, —C₈-C₁₈,—C₈-C₁₆, —C₈-C₁₄, —C₈-C₁₂, —C₈-C₂₀, or —C₆-C₂₄

Non-limiting examples of Formula VII include:

The disclosure also provides a prodrug of Formula VII′:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R⁵³ and R⁵⁴ are independently selected from: —C(O)R⁴, —C(O)A, andhydrogen, each of which except hydrogen can be optionally substitutedwith R⁵;

R⁵⁶ is selected from:

-   -   (i) R⁵⁷;    -   (ii) —NH—C₄-C₃₀alkenyl-C(O)R⁵⁷, —NH—C₄-C₃₀alkynyl-C(O)R⁵⁷,        —NH—C₄-C₃₀alkenylalkynyl-C(O)R⁵⁷, —NH—C₂-C₃₀alkyl-C(O)R⁵⁷,        —O—C₄-C₃₀alkenyl-C(O)R⁵⁷, —O—C₄-C₃₀alkynyl-C(O)R⁵⁷,        —O—C₄-C₃₀alkenylalkynyl-C(O)R⁵⁷, —O—C₂-C₃₀alkyl-C(O)R⁵⁷,        —NH—C₄-C₃₀alkenylR⁵⁷, —NH—C₄-C₃₀alkynylR⁵⁷,        —NH—C₄-C₃₀alkenylalkynylR⁵⁷, —NH—C₂-C₃₀alkylR⁵⁷,        —O—C₄-C₃₀alkenylR⁵⁷, —O—C₄-C₃₀alkynylR⁵⁷,        —O—C₄-C₃₀alkenylalkynylR⁵⁷, and —O—C₂-C₃₀alkylR⁵⁷;    -   (iii) —NH—C₄-C₂₉alkenyl-CH═R⁵⁸, —NH—C₄-C₂₉alkynyl-CH═R⁵⁸,        —NH—C₄-C₂₉alkenylalkynyl-CH═R⁵⁸, —NH—C₂-C₂₉alkyl-CH═R⁵⁸,        —O—C₄-C₂₉alkenyl-CH═R⁵⁸, —O—C₄-C₂₉alkynyl-CH═R⁵⁸,        —O—C₄-C₂₉alkenylalkynyl-CH═R⁵⁸, and —O—C₂-C₂₉alkyl-CH═R⁵⁸;    -   (iv) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid),        polyglycolic acid, or a polyester, polyamide, or other        biodegradable polymer, each of which is substituted with at        least one L⁴-R⁵⁷;    -   (v) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid),        polyglycolic acid, or a polyester, polyamide, or other        biodegradable polymer, each of which is substituted with at        least one moiety of L⁵=R⁵⁸,

wherein R⁵⁶ can be further substituted with R⁵ if valence permits, astable compound is formed, and the resulting compound ispharmaceutically acceptable.

L⁴ is bond, alkyl, alkenyl, alkynyl, —C(O)—, —C(S)—, —NH—, —N(alkyl)-,—O—, or alkyl-C(O)—;

L⁵ is double bond, alkyl, or alkenyl;

In one embodiment, —C₄-C₂₉ as used in the definition of R⁵⁶ is —C₄-C₂₈,—C₄-C₂₆, —C₄-C₂₄, —C₆-C₂₂, —C₆-C₂₀, —C₈-C₁₈, —C₈-C₁₆, —C₈-C₁₄, or—C₈-C₁₂.

R⁵⁷ is selected from:

R⁵⁸ is selected from:

wherein A, R⁴, R⁵, R¹⁵, L¹, and L² are defined above.

Non-limiting examples of compounds of Formula VII′ include:

The disclosure also provides a prodrug of Formula VIII:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof. This structure is related to Sunitinib (marketed inthe form of the (−)-malic acid salt as SUTENT® by Pfizer, and previouslyknown as SU11248), which is an oral, small-molecule, multi-targetedreceptor tyrosine kinase (RTK) inhibitor that was approved by the FDAfor the treatment of renal cell carcinoma (RCC) and imatinib-resistantgastrointestinal stromal tumor (GIST) on Jan. 26, 2006. Sunitinib wasthe first cancer drug simultaneously approved for two differentindications. Sunitinib inhibits cellular signaling by targeting multiplereceptor tyrosine kinases (RTKs). These include all receptors forplatelet-derived growth factor (PDGF-Rs) and vascular endothelial growthfactor receptors (VEGFRs), which play a role in both tumor angiogenesisand tumor cell proliferation. The simultaneous inhibition of thesetargets leads to both reduced tumor vascularization and cancer celldeath, and, ultimately, tumor shrinkage. Sunitinib and derivativesthereof are described in U.S. Pat. Nos. 7,211,600; 6,573,293; and7,125,905.

R¹⁴ is selected from:

The disclosure also provides a prodrug of Formula IX:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R¹⁸ is selected from: —C(O)CH₂CH₂C₁₉-C₃₀alkylR⁵,—C(O)CH₂CH₂C₁₉-C₃₀alkenylR⁵, —C(O)CH₂CH₂C₁₉-C₃₀alkynylR⁵,—C(O)CH₂CH₂C₁₉-C₃₀alkenylalkynylR⁵, —C(O)CH₂CH₂C₁₉-C₃₀alkyl,—C(O)CH₂CH₂C₁₉-C₃₀alkenyl, —C(O)CH₂CH₂C₁₉-C₃₀alkynyl,—C(O)CH₂CH₂C₁₉-C₃₀alkenylalkynyl, and R¹⁹ wherein R¹⁸ can be furtheroptionally further substituted with R⁵ (including for example a secondR⁵) if valence permits, a stable compound is formed, and the resultingcompound is pharmaceutically acceptable;

In various different embodiments, —C₁₉-C₃₀ as used in the definition ofR¹⁸ is —C₁₉-C₂₈, —C₁₉-C₂₆, —C₁₉-C₂₄, —C₁₉-C₂₂, —C₁₉-C₂₀, —C₂₀-C₂₈,—C₂₀-C₂₆, —C₂₀-C₂₄, —C₂₀-C₂₂, —C₂₂-C₂₈, —C₂₂-C₂₆, —C₂₂-C₂₄, or —C₂₆-C₂₈.

R¹⁹ is selected from:

-   -   (i) an unsaturated fatty acid residue including but not limited        to the carbonyl fragment taken from docosahexaenoic acid        (—C(O)(CH₂)₂(CHCHCH₂)₆CH₃)), docosatetraenoic acid, euric acid,        or nervonic acid;    -   (ii) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, or poly(lactic-co-glycolic acid)        including:

or polyglycolic acid, or a polyester, polyamide, or other biodegradablepolymer, each of which can be capped to complete the terminal valence orto create a terminal ether.

The disclosure also provides a prodrug of Formula X:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R²⁰ is selected from: —C(O)CH₂CH₂C₉-C₃₀alkylR⁵,—C(O)CH₂CH₂C₉-C₃₀alkenylR⁵, —C(O)CH₂CH₂C₉-C₃₀alkynylR⁵,—C(O)CH₂CH₂C₉-C₃₀alkenylalkynylR⁵, —C(O)CH₂CH₂C₉-C₃₀alkyl,—C(O)CH₂CH₂C₉-C₃₀alkenyl, —C(O)CH₂CH₂C₉-C₃₀alkynyl,—C(O)CH₂CH₂C₉-C₃₀alkenylalkynyl, and R²¹.

In one embodiment, —C₉-C₃₀ as used in the definition of R²⁰ is —C₁₀-C₂₈,—C₁₁-C₂₆, —C₁₁-C₂₄, —C₁₂-C₂₂, —C₁₂-C₂₀, —C₁₂-C₁₈, —C₁₂-C₁₆, or —C₁₂-C₁₄

R²¹ is selected from:

-   -   (i) an unsaturated fatty acid residue including but not limited        the carbonyl fragment taken from linoleic acid        (—C(O)(CH₂)₇(CH)₂CH₂(CH)₂(CH₂)₄CH₃)), docosahexaenoic acid        (—C(O)(CH₂)₂(CHCHCH₂)₆CH₃)), eicosapentaenoic acid        (—C(O)(CH₂)₃(CHCHCH₂)₅CH₃)), alpha-linolenic acid        (—C(O)(CH₂)₇(CHCHCH₂)₃CH₃)) stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid and mead acid, each of which can        be further substituted with R⁵ if valence permits, a stable        compound is formed, and the resulting compound is        pharmaceutically acceptable;    -   (ii) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid)        including:

or polyglycolic acid, or a polyester, polyamide, or other biodegradablepolymer, each of which can be capped to complete the terminal valence orto create a terminal ether.

The disclosure also provides a prodrug of Formula XI:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

Q is selected from: N, CH, and CR²³.

R²² is selected from: —C(O)CH₂CH₂C₁₁-C₃₀alkylR⁵,—C(O)CH₂CH₂C₁₁-C₃₀alkenylR⁵, —C(O)CH₂CH₂C₁₁-C₃₀alkynylR⁵,—C(O)CH₂CH₂C₁₁-C₃₀alkenylalkynylR⁵, —C(O)CH₂CH₂C₁₁-C₃₀alkyl,—C(O)CH₂CH₂C₁₁-C₃₀alkenyl, —C(O)CH₂CH₂C₁₁-C₃₀alkynyl,—C(O)CH₂CH₂C₁₁-C₃₀alkenylalkynyl and R²¹ and wherein R²² can be furthersubstituted with R⁵ (including for example a second R⁵) if valencepermits, a stable compound is formed, and the resulting compound ispharmaceutically acceptable.

In one embodiment, —C₁₁-C₃₀ as used in the definition of R²² is—C₁₂-C₂₈, —C₁₃-C₂₆, —C₁₃-C₂₄, —C₁₃-C₂₂, —C₁₃-C₂₀, —C₁₃-C₁₈, —C₁₃-C₁₆, or—C₁₃-C₁₄.

R²³, R²⁴, and R²⁵ are independently selected from: hydrogen, halogen,hydroxyl, cyano, mercapto, nitro, amino, aryl, alkyl, alkoxy, alkenyl,alkynyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, —S(O)₂alkyl,—S(O)alkyl, —P(O)(Oalkyl)₂, B(OH)₂, —Si(CH₃)₃, —COOH, —COOalkyl, —CONH₂,

each of which except halogen, nitro, and cyano, may be optionallysubstituted, for example with halogen, alkyl, aryl, heterocycle orheteroaryl.

R²⁶ is selected from H, C(O)A, —C₀-C₁₀alkylR⁵, —C₂-C₁₀alkenylR⁵,—C₂-C₁₀alkynylR⁵, —C₂-C₁₀alkenyl, and —C₂-C₁₀alkynyl.

In one embodiment, —C₂-C₁₀ as used in R²⁶ is —C₄-C₁₀, —C₆-C₁₀, or—C₈-C₁₀.

The disclosure also provides a prodrug of Formula XII:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R²⁷ is selected from: —C(O)CH₂CH₂C₀-C₃₀alkylR⁵,—C(O)CH₂CH₂C₀-C₃₀alkenylR⁵, —C(O)CH₂CH₂C₀-C₃₀alkynylR⁵,—C(O)CH₂CH₂C₀-C₃₀alkenylalkynylR⁵, —C(O)CH₂CH₂C₀-C₃₀alkyl,—C(O)CH₂CH₂C₀-C₃₀alkenyl, —C(O)CH₂CH₂C₀-C₃₀alkynyl,—C(O)CH₂CH₂C₀-C₃₀alkenylalkynyl, and R²¹.

In various different embodiments, —C₀-C₃₀ as used in R²⁷ is —C₀-C₂₈,—C₀-C₂₆, —C₀-C₂₄, —C₀-C₂₂, —C₀-C₂₀, —C₀-C₁₈, —C₀-C₁₆, —C₀-C₁₄, —C₀-C₁₂,or —C₀-C₁₁, —C₀-C₁₀, —C₀-C₈, —C₀-C₆, —C₀-C₄, —C₀-C₂, —C₂-C₂₈, —C₄-C₂₆,—C₄-C₂₄, —C₄-C₂₂, —C₄-C₂₀, —C₆-C₁₈, —C₆-C₁₆, —C₆-C₁₄, —C₆-C₁₂, —C₄-C₁₁,—C₀-C₁₀, —C₀-C₈, —C₀-C₆, —C₀-C₄, or —C₀-C₂.

The disclosure also provides a prodrug of Formula XIV:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R³⁰ is selected from: polyethylene glycol, polypropylene glycol,polypropylene oxide, polylactic acid, poly(lactic-co-glycolic acid), apolyglycolic acid, a polyester, a polyamide,

and other biodegradable polymers, wherein R³⁰ is optionally substitutedwith R³¹, and wherein each R³⁰ with a terminal hydroxy or carboxy groupcan be substituted to create an ether or ester;

R³¹ is hydrogen, A, —COOH, —C(O)A, aryl, alkyl, alkoxy, alkenyl, alkynylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, polyethylene glycol, or

wherein x, y, and A are defined above.

The disclosure also provides a prodrug of Formula XV:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R³² is selected from: R³⁵, R⁵¹, alkyl, alkyloxy, polyethylene glycol,polypropylene glycol, polypropylene oxide, polylactic acid,poly(lactic-co-glycolic acid), a polyglycolic acid, a polyester,polyamide, or other biodegradable polymer, wherein each R³² other thanR³⁵ and R⁵¹ is substituted with at least one L⁴-R⁵¹;

wherein R³² can be further substituted with R⁵ if valence permits, astable compound is formed, and the resulting compound ispharmaceutically acceptable.

R³⁵ is selected from:

R⁵¹ is selected from

R⁵³ and R⁵⁴ are independently selected from: —C(O)R⁴, C(O)A, andhydrogen, each of which except hydrogen can be optionally substitutedwith R⁵;

R⁵⁵ is selected from:

-   -   (i) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid),        polyglycolic acid, or a polyester, a polyamide, or other        biodegradable polymer, wherein a terminal hydroxy or carboxy        group can be substituted to create an ether or ester,        respectively;    -   (ii) —C₁₀-C₃₀alkylR⁵, —C₁₀-C₃₀alkenylR⁵, —C₁₀-C₃₀alkynylR⁵,        —C₁₀-C₃₀alkenylalkynylR⁵, —C₁₀-C₃₀alkyl, —C₁₀-C₃₀alkenyl,        —C₁₀-C₃₀alkynyl, —C₁₀-C₃₀alkenylalkynyl;    -   (iii) an unsaturated fatty acid residue including but not        limited the carbon fragment taken from linoleic acid        (—(CH₂)₈(CH)₂CH₂(CH)₂(CH₂)₄CH₃)), docosahexaenoic acid        (—(CH₂)₃(CHCHCH₂)₆CH₃)), eicosapentaenoic acid        (—(CH₂)₄(CHCHCH₂)₅CH₃)), alpha-linolenic acid        (—(CH₂)₈(CHCHCH₂)₃CH₃)) stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid or mead acid;    -   (iv) alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,        heterocycloalkyl, arylalkyl, heteroarylalkyl;

wherein A, x, y, R⁵, L¹, and L² are defined above.

Non-limiting examples of R⁵⁵ include:

The disclosure also provides a prodrug of Formula XVI:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R³³ is selected from: carbonyl linked polyethylene glycol, carbonyllinked polypropylene glycol, carbonyl linked polypropylene oxide,polylactic acid, and poly(lactic-co-glycolic acid), a polyglycolic acid,a polyester, polyamide,

or other biodegradable polymer, wherein each R³³ is optionallysubstituted with R³¹, and wherein each of R³³ with a terminal hydroxy orcarboxy group can be substituted to create an ether or ester,respectively.

In one embodiment R³¹ is —C(O)A, alkyl, or PEG.

In one embodiment R³¹ is —C(O)A, wherein A is methyl.

In one embodiment R³³ is

The disclosure also provides a prodrug of Formula XVII:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R³⁴ is selected from: R³⁶, carbonyl linked polyethylene glycol, carbonyllinked polypropylene glycol, carbonyl linked polypropylene oxide,polylactic acid, and poly(lactic-co-glycolic acid), a polyglycolic acid,a polyester, polyamide,

or other biodegradable polymer, wherein each R³⁴ other than R³⁶ issubstituted with at least one L⁴-R⁵²;

R³⁶ is selected from:

R⁵² is selected from

z is 0, 1, 2, 3, 4, or 5;

R⁵³ and R⁵⁴ are independently selected from: —C(O)R⁴, C(O)A, andhydrogen, each of which except hydrogen can be optionally substitutedwith R⁵;

R⁵⁵ is selected from:

-   -   (i) polyethylene glycol, polypropylene glycol, polypropylene        oxide, polylactic acid, and poly(lactic-co-glycolic acid),        polyglycolic acid, or a polyester, a polyamide, or other        biodegradable polymers, wherein a terminal hydroxy or carboxy        group can be substituted to create an ether or ester,        respectively;    -   (ii) —C₁₀-C₃₀alkylR⁵, —C₁₀-C₃₀alkenylR⁵, —C₁₀-C₃₀alkynylR⁵,        —C₁₀-C₃₀alkenylalkynylR⁵, —C₁₀-C₃₀alkyl, —C₁₀-C₃₀alkenyl,        —C₁₀-C₃₀alkynyl, —C₁₀-C₃₀alkenylalkynyl;    -   (iii) an unsaturated fatty acid residue including but not        limited the carbon fragment taken from linoleic acid        (—(CH₂)₈(CH)₂CH₂(CH)₂(CH₂)₄CH₃)), docosahexaenoic acid        (—(CH₂)₃(CHCHCH₂)₆CH₃)), eicosapentaenoic acid        (—(CH₂)₄(CHCHCH₂)₅CH₃)), alpha-linolenic acid        (—(CH₂)₈(CHCHCH₂)₃CH₃)) stearidonic acid, y-linolenic acid,        arachidonic acid, docosatetraenoic acid, palmitoleic acid,        vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic        acid, euric acid, nervonic acid or mead acid;    -   (iv) alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,        heterocycloalkyl, arylalkyl, heteroarylalkyl;

wherein A, x, y, R⁵, L¹, and L² are defined above.

The disclosure also provides a prodrug of Formula XVIII or Formula XIX:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R³⁷ is selected from: R³⁸, polyethylene glycol, polypropylene glycol,polypropylene oxide, polylactic acid, poly(lactic-co-glycolic acid), apolyglycolic acid, a polyester, a polyamide, or other biodegradablepolymer, wherein each R³⁷ other than R³⁸ is substituted with at leastone L⁴-R⁵⁹;

L⁶ is selected from —O—, —NH—, —N(alkyl)₁₋₄-, —C(O)O—, —S—, —C(O)— and—OC(O)—;

R³⁸ is selected from:

and

R⁵⁹ is selected from

wherein x, y, R²⁴, R²⁵, R²⁶, and L⁴ are as defined above.

The disclosure also provides a prodrug of Formula XX, Formula XXI,Formula XXII, Formula XXIII:

or a pharmaceutically acceptable composition, salt, or isotopicderivative thereof.

R³⁹ is selected from: R⁴⁰, carbonyl linked polyethylene glycol, carbonyllinked polypropylene glycol, carbonyl linked polypropylene oxide,polylactic acid, and poly(lactic-co-glycolic acid), a polyglycolic acid,a polyester, polyamide,

or other biodegradable polymer, wherein each R³⁹ other than R⁴⁰ issubstituted with at least one L⁴-R⁶⁰;

R⁴⁰ is selected from:

R⁶⁰ is selected from:

In an alternative embodiment, a

moiety in a R group that can be substituted with R⁵ as defined herein isinstead substituted with oxo to form

In another alternative embodiment, x is 0.

In another alternative embodiment, y is 0.

In another embodiment, a compound selected from the following isprovided:

wherein R¹⁵ is as defined above and R¹⁰ or R⁴² is selected from:—NHC(O)C₁₋₂₀alkyl, —NHC(O)C₁₋₂₀alkenyl, —NHC(O)C₁₋₂₀alkynyl,—NHC(O)(C₁₋₂₀alkyl with at least one R⁵ substituent on the alkyl chain),—NHC(O)(C₁₋₂₀alkenyl, with at least one R⁵ substituent on the alkenylchain) —NHC(O)(C₁₋₂₀alkynyl, with at least one R⁵ substituent on thealkynyl chain), —NH(lactic acid)₂₋₂₀C(O)C₁₋₂₀alkyl, —NH(lacticacid)₂₋₁₀C(O)C₁₋₂₀alkyl, —NH(lactic acid)₄₋₂₀C(O)C₁₋₂₀alkyl, —NH(lacticacid)₂₋₂₀C(O)C₁₋₁₀alkyl, —NH(lactic acid)₂₋₂₀C(O)_(C4-10)alkyl,—NH(lactic acid)₂₋₂₀C(O)OH, —NH(lactic acid)₂₋₁₀C(O)OH, —NH(lacticacid)₄₋₂₀C(O)OH, —NH(lactic acid)₂₋₁₀C(O)OH, —NH(lactic acid)₄₋₁₀C(O)OH,—NH(lactide-co-glycolide)₂₋₁₀C(O)_(C1-20)alkyl,—NH(lactide-co-glycolide)₄₋₁₀C(O)_(C1-20)alkyl,—NH(lactide-co-glycolide)₂₋₁₀C(O)_(C1-10)alkyl,—NH(lactide-co-glycolide)₂₋₁₀C(O)_(C4-20)alkyl, —NH(glycolicacid)₂₋₁₀C(O)_(C1-10)alkyl, —NH(glycolic acid)₄₋₁₀C(O)_(C1-10)alkyl,—NH(lactic acid)₄₋₁₀C(O)_(C1-10)alkyl, —NH(lacticacid)₂₋₁₀C(O)_(C1-10)alkyl, NH(lactic acid)₂₋₁₀C(O)_(C4-10)alkyl,—NH(lactic acid)₂₋₁₀C(O)_(C4-10)alkyl, and —NH(lacticacid)₂₋₁₀C(O)_(C4-10)alkyl.

Pharmaceutical compositions comprising a compound or salt of Formula I,Formula II, Formula II′, Formula III, Formula IV, Formula V, Formula VI,Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII, FormulaVII′, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIIItogether with a pharmaceutically acceptable carrier are also disclosed.

Methods of treating or preventing ocular disorders, including glaucoma,a disorder mediated by carbonic anhydrase, a disorder or abnormalityrelated to an increase in intraocular pressure (IOP), a disordermediated by nitric oxide synthase (NOS), a disorder requiringneuroprotection such as to regenerate/repair optic nerves, allergicconjunctivitis, anterior uveitis, cataracts, dry or wet age-relatedmacular degeneration (AMD) or diabetic retinopathy are disclosedcomprising administering a therapeutically effective amount of acompound or salt or Formula I, Formula II, Formula II′, Formula III,Formula IV, Formula V, Formula VI, Formula III′, Formula IV′, FormulaV′, Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula IX,Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, FormulaXVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,Formula XXII, or Formula XXIII to a host, including a human, in need ofsuch treatment.

In another embodiment, an effective amount of a compound of Formula I,Formula II, Formula II′, Formula III, Formula IV, Formula V, Formula VI,Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII, FormulaVII′, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIII isprovided to decrease intraocular pressure (IOP) caused by glaucoma. Inan alternative embodiment, the compound of Formula I, Formula II,Formula II′, Formula III, Formula IV, Formula V, Formula VI, FormulaIII′, Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′,Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, FormulaXIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,Formula XX, Formula XXI, Formula XXII, or Formula XXIII can be used todecrease intraocular pressure (IOP), regardless of whether it isassociated with glaucoma.

In one embodiment, the disorder is associated with an increase inintraocular pressure (IOP) caused by potential or previously poorpatient compliance to glaucoma treatment. In yet another embodiment, thedisorder is associated with potential or poor neuroprotection throughneuronal nitric oxide synthase (NOS). The active compound or its salt orprodrug provided herein may thus dampen or inhibit glaucoma in a host,by administration of an effective amount in a suitable manner to a host,typically a human, in need thereof.

Methods for the treatment of a disorder associated with glaucoma,increased intraocular pressure (IOP), and optic nerve damage caused byeither high intraocular pressure (IOP) or neuronal nitric oxide synthase(NOS) are provided that includes the administration of an effectiveamount of a compound Formula I, Formula II, Formula II′, Formula III,Formula IV, Formula V, Formula VI, Formula III′, Formula IV′, FormulaV′, Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula IX,Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, FormulaXVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,Formula XXII, or Formula XXIII or a pharmaceutically acceptable saltthereof, optionally in a pharmaceutically acceptable carrier are alsodisclosed.

Methods for the treatment of a disorder associated with age-relatedmacular degeneration (AMD) are provided that includes the administrationof an effective amount of a compound Formula I, Formula II, Formula II′,Formula III, Formula IV, Formula V, Formula VI, Formula III′, FormulaIV′, Formula V′, Formula VI′, Formula VII, Formula VII′, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV,Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX,Formula XXI, Formula XXII, or Formula XXIII or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier are also disclosed.

Methods for treatment of a disorder that using a carbonic anhydraseinhibitor to treat a patient in need thereof also disclosed.

The present invention includes at least the following features:

-   -   (a) a compound of Formula I, Formula II, Formula II′, Formula        III, Formula IV, Formula V, Formula VI, Formula III′, Formula        IV′, Formula V′, Formula VI′, Formula VII, Formula VII′, Formula        VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula        XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,        Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula        XXIII as described herein, and pharmaceutically acceptable salts        and prodrugs thereof (each of which and all subgenuses and        species thereof are considered individually and specifically        described);    -   (b) Formula I, Formula II, Formula II′, Formula III, Formula IV,        Formula V, Formula VI, Formula III′, Formula IV′, Formula V′,        Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula        IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV,        Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula        XX, Formula XXI, Formula XXII, or Formula XXIII as described        herein, and pharmaceutically acceptable salts and prodrugs        thereof, for use in treating or preventing an ocular disorder as        further described herein;    -   (c) Formula I, Formula II, Formula II′, Formula III, Formula IV,        Formula V, Formula VI, Formula III′, Formula IV′, Formula V′,        Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula        IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV,        Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula        XX, Formula XXI, Formula XXII, or Formula XXIII as described        herein, and pharmaceutically acceptable salts and prodrugs        thereof, for use in treating or preventing disorders related to        an ocular disorder such as glaucoma, a disorder mediated by        carbonic anhydrase, a disorder or abnormality related to an        increase in intraocular pressure (IOP), a disorder mediated by        nitric oxide synthase (NOS), a disorder requiring        neuroprotection such as to regenerate/repair optic nerves,        allergic conjunctivitis, anterior uveitis, cataracts, dry or wet        age-related macular degeneration (AMD) or diabetic retinopathy;    -   (d) use of Formula I, Formula II, Formula II′, Formula III,        Formula IV, Formula V, Formula VI, Formula III′, Formula IV′,        Formula V′, Formula VI′, Formula VII, Formula VII′, Formula        VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula        XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,        Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula        XXIII and pharmaceutically acceptable salts and prodrugs thereof        in the manufacture of a medicament for use in treating or        preventing glaucoma and disorders involving increased        intraocular pressure (IOP) or nerve damage related to either IOP        or nitric oxide synthase (NOS) and other disorders described        further herein;    -   (e) use of Formula I, Formula II, Formula II′, Formula III,        Formula IV, Formula V, Formula VI, Formula III′, Formula IV′,        Formula V′, Formula VI′, Formula VII, Formula VII′, Formula        VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula        XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,        Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula        XXIII and pharmaceutically acceptable salts and prodrugs thereof        in the manufacture of a medicament for use in treating or        preventing age-related macular degeneration (AMD) and other        disorders described further herein;    -   (f) a process for manufacturing a medicament intended for the        therapeutic use for treating or preventing glaucoma and        disorders involving nerve damage related to both (IOP) and        nitric oxide synthase (NOS) and other disorders described        further herein characterized in that Formula I, Formula II,        Formula II′, Formula III, Formula IV, Formula V, Formula VI,        Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII,        Formula VII′, Formula VIII, Formula IX, Formula X, Formula XI,        Formula XII, Formula XIV, Formula XV, Formula XVI, Formula XVII,        Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula        XXII, or Formula XXIII as described herein is used in the        manufacture;    -   (g) a pharmaceutical formulation comprising an effective        host-treating amount of the Formula I, Formula II, Formula II′,        Formula III, Formula IV, Formula V, Formula VI, Formula III′,        Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′,        Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,        Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula        XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, or        Formula XXIII or a pharmaceutically acceptable salt or prodrug        thereof together with a pharmaceutically acceptable carrier or        diluent;    -   (h) Formula I, Formula II, Formula II′, Formula III, Formula IV,        Formula V, Formula VI, Formula III′, Formula IV′, Formula V′,        Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula        IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV,        Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula        XX, Formula XXI, Formula XXII, or Formula XXIII as described        herein in substantially pure form, (e.g., at least 90 or 95%);    -   (i) processes for the manufacture of the compounds Formula I,        Formula II, Formula II′, Formula III, Formula IV, Formula V,        Formula VI, Formula III′, Formula IV′, Formula V′, Formula VI′,        Formula VII, Formula VII′, Formula VIII, Formula IX, Formula X,        Formula XI, Formula XII, Formula XIV, Formula XV, Formula XVI,        Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula        XXI, Formula XXII, or Formula XXIII and salts, compositions,        dosage forms thereof; and    -   (j) processes for the preparation of therapeutic products        including drug delivery agents that contain an effective amount        of Formula I, Formula II, Formula II′, Formula III, Formula IV,        Formula V, Formula VI, Formula III′, Formula IV′, Formula V′,        Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula        IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV,        Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula        XX, Formula XXI, Formula XXII, or Formula XXIII as described        herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the stability of brinzolamide at physiologicalconditions (37° C.) and at accelerated degradation conditions (50° C.)over 14 days. The x-axis represents time (days) and the y-axisrepresents the amount of undegraded brinzolamide as a percentage of thetotal brinzolamide amount as analyzed by RP-HPLC.

FIG. 2 illustrates the stability of brinzolamide-PLA (n=1) (32-3) atphysiological conditions (37° C.) over 14 days. The x-axis representstime (days) and the y-axis represents the amount of undegradedbrinzolamide-PLA (n=1) (32-3) as a percentage of the total brinzolamideamount as analyzed by RP-HPLC.

FIG. 3 illustrates the percentage of brinzolamide-PLA (n=2) (33-2) thatis degraded to brinzolamide-PLA (n=1) (32-3) at physiological conditions(37° C.) over 14 days. The x-axis represents time (days) and the y-axisrepresents the amount of each undegraded brinzolamide-PLA analog as apercentage of the total brinzolamide amount as analyzed by RP-HPLC.

FIG. 4 illustrates the percentage of brinzolamide-PLA (n=3) (34-2) thatis degraded to brinzolamide-PLA (n=2) (33-2), brinzolamide-PLA (n=1)(32-3), and parent brinzolamide at physiological conditions (37° C.)over 19 days. The x-axis represents time (days) and the y-axisrepresents the amount of each undegraded brinzolamide-PLA analog as apercentage of the total brinzolamide amount as analyzed by RP-HPLC.

FIG. 5 illustrates the percentage of brinzolamide-PLA (n=4) (35-2) thatis degraded to brinzolamide-PLA (n=3) (34-2), brinzolamide-PLA (n=2)(33-2), brinzolamide-PLA (n=1) (32-3), and parent brinzolamide atphysiological conditions (37° C.) over 19 days. The x-axis representstime (days) and the y-axis represents the amount of each undegradedbrinzolamide-PLA analog as a percentage of the total brinzolamide amountas analyzed by RP-HPLC.

FIG. 6 illustrates the percentage of brinzolamide-acetyl PLA (n=3)(36-1) that is degraded to brinzolamide-PLA (n=2) (33-2),brinzolamide-PLA (n=1) (32-3), and parent brinzolamide at physiologicalconditions (37° C.) over 19 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded brinzolamide-PLAanalog as a percentage of the total brinzolamide amount as analyzed byRP-HPLC.

FIG. 7 illustrates the percentage of brinzolamide-t-butyl PLA (n=3)(40-1) that is degraded to brinzolamide-PLA (n=2) (33-2),brinzolamide-PLA (n=1) (32-3), and parent brinzolamide at physiologicalconditions (37° C.) over 19 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded brinzolamide-PLAanalog as a percentage of the total brinzolamide amount as analyzed byRP-HPLC.

FIG. 8 illustrates the percentage of brinzolamide-acetyl PLA (n=4)(37-1) that is degraded to brinzolamide-PLA (n=3) (34-2),brinzolamide-PLA (n=2) (33-2), brinzolamide-PLA (n=1) (32-3), and parentbrinzolamide at physiological conditions (37° C.) over 19 days. Thex-axis represents time (days) and the y-axis represents the amount ofeach undegraded brinzolamide-PLA analog as a percentage of the totalbrinzolamide amount as analyzed by RP-HPLC.

FIG. 9 illustrates the percentage of brinzolamide-acetyl PLA (n=5)(38-1) that is degraded to brinzolamide-PLA (n=3) (34-2),brinzolamide-PLA (n=2) (33-2), brinzolamide-PLA (n=1) (32-3), and parentbrinzolamide at physiological conditions (37° C.) over 19 days. Thex-axis represents time (days) and the y-axis represents the amount ofeach undegraded brinzolamide-PLA analog as a percentage of the totalbrinzolamide amount as analyzed by RP-HPLC.

FIG. 10 illustrates the percentage of brinzolamide-acetyl PLA (n=6)(39-1) that is degraded to brinzolamide-PLA (n=4) (35-2),brinzolamide-PLA (n=2) (33-2), brinzolamide-PLA (n=1) (32-3), and parentbrinzolamide at physiological conditions (37° C.) over 19 days. Thex-axis represents time (days) and the y-axis represents the amount ofeach undegraded brinzolamide-PLA analog as a percentage of the totalbrinzolamide amount as analyzed by RP-HPLC.

FIG. 11 illustrates the stability of dorzolamide at physiologicalconditions (37° C.) and at accelerated degradation conditions (60° C.)over 14 days. The x-axis represents time (days) and the y-axisrepresents the amount of undegraded dorzolamide as a percentage of thetotal dorzolamide amount as analyzed by RP-HPLC.

FIG. 12 illustrates the percentage of dorzolamide-PLA (n=1) (19-3) thatis degraded to dorzolamide at physiological conditions (37° C.) over 14days. The x-axis represents time (days) and the y-axis represents theamount of each undegraded dorzolamide-PLA analog as a percentage of thetotal dorzolamide amount as analyzed by RP-HPLC.

FIG. 13 illustrates the percentage of dorzolamide-PLA (n=3) (20-2) thatis degraded to dorzolamide-PLA (n=2), dorzolamide-PLA (n=1) (19-3), andparent dorzolamide at physiological conditions (37° C.) over 14 days.The x-axis represents time (days) and the y-axis represents the amountof each undegraded dorzolamide-PLA analog as a percentage of the totaldorzolamide amount as analyzed by RP-HPLC.

FIG. 14 illustrates the percentage of dorzolamide-PLA (n=4) (21-2) thatis degraded to dorzolamide-PLA (n=3) (20-2), dorzolamide-PLA (n=2),dorzolamide-PLA (n=1) (19-3), and parent dorzolamide at physiologicalconditions (37° C.) over 14 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded dorzolamide-PLAanalog as a percentage of the total dorzolamide amount as analyzed byRP-HPLC.

FIG. 15 illustrates the percentage of dorzolamide-acetyl PLA (n=3)(27-1) that is degraded to dorzolamide-PLA (n=3) (20-2), dorzolamide-PLA(n=2), dorzolamide-PLA (n=1) (19-3), and parent dorzolamide atphysiological conditions (37° C.) over 14 days. The x-axis representstime (days) and the y-axis represents the amount of each undegradeddorzolamide-PLA analog as a percentage of the total dorzolamide amountas analyzed by RP-HPLC.

FIG. 16 illustrates the percentage of dorzolamide-acetyl PLA (n=5)(28-1) that is degraded to dorzolamide-PLA (n=3) (20-2), dorzolamide-PLA(n=2), dorzolamide-PLA (n=1) (19-3), and parent dorzolamide atphysiological conditions (37° C.) over 14 days. The x-axis representstime (days) and the y-axis represents the amount of each undegradeddorzolamide-PLA analog as a percentage of the total dorzolamide amountas analyzed by RP-HPLC.

FIG. 17 illustrates the percentage of dorzolamide-acetyl PLA (n=6)(29-1) that is degraded to dorzolamide-PLA (n=4) (21-2), dorzolamide-PLA(n=2), dorzolamide-PLA (n=1) (19-3), and parent dorzolamide atphysiological conditions (37° C.) over 14 days. The x-axis representstime (days) and the y-axis represents the amount of each undegradeddorzolamide-PLA analog as a percentage of the total dorzolamide amountas analyzed by RP-HPLC.

FIG. 18 illustrates the stability of latanoprost at physiologicalconditions (37° C.) and at accelerated degradation conditions (60° C.)over 14 days. The x-axis represents time (days) and the y-axisrepresents the amount of undegraded latanoprost as a percentage of thetotal latanoprost amount as analyzed by RP-HPLC.

FIG. 19 illustrates the percentage of latanoprost-PLA (n=3) (43-2) thatis degraded to latanoprost-PLA (n=2), latanoprost-PLA (n=1), and parentlatanoprost at physiological conditions (37° C.) over 14 days. Thex-axis represents time (days) and the y-axis represents the amount ofeach undegraded latanoprost-PLA analog as a percentage of the totallatanoprost amount as analyzed by RP-HPLC.

FIG. 20 illustrates the percentage of latanoprost-acetyl PLA (n=4)(44-1) that is degraded to latanoprost-PLA (n=3), latanoprost-PLA (n=2),latanoprost-PLA (n=1), and parent latanoprost at physiologicalconditions (37° C.) over 14 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded latanoprost-PLAanalog as a percentage of the total latanoprost amount as analyzed byRP-HPLC.

FIG. 21 illustrates the percentage of latanoprost-acetyl PLA (n=5)(45-1) that is degraded to latanoprost-PLA (n=3), latanoprost-PLA (n=2),latanoprost-PLA (n=1), and parent latanoprost at physiologicalconditions (37° C.) over 14 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded latanoprost-PLAanalog as a percentage of the total latanoprost amount as analyzed byRP-HPLC.

FIG. 22 illustrates the percentage of latanoprost-acetyl PLA (n=6)(46-1) that is degraded to latanoprost-PLA (n=4), latanoprost-PLA (n=2),latanoprost-PLA (n=1), and parent latanoprost at physiologicalconditions (37° C.) over 14 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded latanoprost-PLAanalog as a percentage of the total latanoprost amount as analyzed byRP-HPLC.

FIG. 23A illustrates the percentage of brinzolamide-PLA(n=4)-succinate-5-hydroxy-Sunitinib (60-1) that is degraded tobrinzolamide-PLA (n=3) (34-2), brinzolamide-PLA (n=2) (33-2),brinzolamide-PLA (n=1) (32-3), and parent brinzolamide at physiologicalconditions (37° C.) over 7 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded brinzolamide-PLAanalog as a percentage of the total brinzolamide amount as analyzed byRP-HPLC.

FIG. 23B illustrate the percentage of brinzolamide-PLA(n=4)-succinate-5-hydroxy-Sunitinib (60-1) that is degraded tobrinzolamide-PLA (n=3) (34-2), brinzolamide-PLA (n=2) (33-2),brinzolamide-PLA (n=1) (32-3), and parent brinzolamide at accelerateddegradation conditions (50° C.) over 7 days. The x-axis represents time(days) and the y-axis represents the amount of each undegradedbrinzolamide-PLA analog as a percentage of the total brinzolamide amountas analyzed by RP-HPLC.

FIG. 24A illustrates the percentage of dorzolamide-PLA(n=4)-succinate-5-hydroxy-Sunitinib (58-5) that is degraded todorzolamide-PLA (n=3) (20-2), dorzolamide-PLA (n=2), dorzolamide-PLA(n=1) (19-3), and parent dorzolamide at physiological conditions (37°C.) over 14 days. The x-axis represents time (days) and the y-axisrepresents the amount of each undegraded dorzolamide-PLA analog as apercentage of the total dorzolamide amount as analyzed by RP-HPLC.

FIG. 24B illustrates the percentage of dorzolamide-PLA(n=4)-succinate-5-hydroxy-Sunitinib (58-5) that is degraded todorzolamide-PLA (n=3) (20-2), dorzolamide-PLA (n=2), dorzolamide-PLA(n=1) (19-3), and parent dorzolamide at accelerated degradationconditions (50° C.) over 14 days. The x-axis represents time (days) andthe y-axis represents the amount of each undegraded dorzolamide-PLAanalog as a percentage of the total dorzolamide amount as analyzed byRP-HPLC.

FIG. 25A is a light microscopy image at 40× magnification of particlesencapsulating brinzolamide-acetyl PLA (n=5) (38-1)

FIG. 25B is a light microscopy image at 40× magnification of particlesprepared with high polymer concentration (200 mg/mL) encapsulatingbrinzolamide-acetyl PLA (n=5) (38-1)

FIG. 25C is a light microscopy image at 40× magnification of particlesencapsulating dorzolamide-acetyl PLA (n=5) (28-1)

FIG. 25D is a light microscopy image at 40× magnification of particlesencapsulating latanoprost-acetyl PLA (n=5) (45-1)

FIG. 26 illustrates the drug release kinetics of brinzolamide-acetyl PLA(n=5) (38-1) from particles prepared with polymer concentration of 140mg/mL and 200 mg/mL over 14 days. The x-axis represents time (days) andthe y-axis represents the percent of cumulative drug released asanalyzed by RP-HPLC.

FIG. 27 illustrates the drug release kinetics of dorzolamide-acetyl PLA(n=5) (28-1) and latanoprost-Acetyl PLA (n=5) (45-1) from particlesprepared with PLGA microparticles over 6 days. The x-axis representstime (days) and the y-axis represents the percent of cumulative drugreleased as analyzed by RP-HPLC.

DETAILED DESCRIPTION I. Terminology

The presently disclosed subject matter may be embodied in many differentforms and should not be construed as limited to the embodiments setforth herein. Indeed, many modifications and other embodiments of thepresently disclosed subject matter will come to mind for one skilled inthe art to which the presently disclosed subject matter pertains havingthe benefit of the teachings presented in the descriptions includedherein. Therefore, it is to be understood that the presently disclosedsubject matter is not to be limited to the specific embodimentsdisclosed and that modifications and other embodiments are intended tobe included within the scope of the disclosed subject matter.

Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this presently described subject matter belongs.

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein includeenantiomers, mixtures of enantiomers, diastereomers, cis/trans isomers,tautomers, racemates and other isomers, such as rotamers, as if each isspecifically described.

The compounds in any of the Formulas may be prepared by chiral orasymmetric synthesis from a suitable optically pure precursor orobtained from a racemate or mixture of enantiomers or diastereomers byany conventional technique, for example, by chromatographic resolutionusing a chiral column, TLC or by the preparation of diastereoisomers,separation thereof and regeneration of the desired enantiomer ordiastereomer. See, e.g., “Enantiomers, Racemates and Resolutions,” by J.Jacques, A. Collet, and S. H. Wilen, (Wiley-Interscience, New York,1981); S. H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977);E. L. Eliel Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and S. H. Wilen Tables of Resolving Agents and OpticalResolutions 268 (E. L. Eliel ed., Univ. of Notre Dame Press, Notre Dame,Ind., 1972, Stereochemistry of Organic Compounds, Ernest L. Eliel,Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), andStereoselective Synthesis A Practical Approach, Mihály Nógrádi (1995 VCHPublishers, Inc., NY, NY).

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item.Recitation of ranges of values are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. The endpoints of all ranges are includedwithin the range and are independently combinable. All methods describedherein can be performed in a suitable order unless otherwise indicatedherein or otherwise clearly contradicted by context. The use ofexamples, or exemplary language (e.g., “such as”), is intended merely tobetter illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed.

The present invention includes compounds of Formula I, Formula II,Formula II′, Formula III, Formula IV, Formula V, Formula VI, FormulaIII′, Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′,Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, FormulaXIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,Formula XX, Formula XXI, Formula XXII, or Formula XXIII and the use ofcompounds with at least one desired isotopic substitution of an atom, atan amount above the natural abundance of the isotope, i.e., enriched.Isotopes are atoms having the same atomic number but different massnumbers, i.e., the same number of protons but a different number ofneutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I respectively. The invention includesisotopically modified compounds of Formula I, Formula II, Formula II′,Formula III, Formula IV, Formula V, Formula VI, Formula III′, FormulaIV′, Formula V′, Formula VI′, Formula VII, Formula VII′, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV,Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX,Formula XXI, Formula XXII, or Formula XXIII. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures that achieves the desired result. Alternatively orin addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used. In oneembodiment, the isotopic substitution is deuterium for hydrogen at oneor more locations on the molecule to improve the performance of thedrug, for example, the pharmacodynamics, pharmacokinetics,biodistribution, half-life, stability, AUC, T_(max), C_(max), etc. Forexample, the deuterium can be bound to carbon in a location of bondbreakage during metabolism (an α-deuterium kinetic isotope effect) ornext to or near the site of bond breakage (a β-deuterium kinetic isotopeeffect).

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched at any location of interest.In one embodiment deuterium is 90, 95 or 99% enriched at a desiredlocation.

In one embodiment, the substitution of a hydrogen atom for a deuteriumatom can be provided in any of A, L¹, or L². In one embodiment, thesubstitution of a hydrogen atom for a deuterium atom occurs within an Rgroup selected from any of R, R¹, R², R³, R⁴′ R⁵, R⁶, R^(6′), R⁷, R⁸,R^(8′), R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ R²⁰, R²¹, R²², R²³,R²⁴, R²⁵, R²⁶, R²⁷, R³¹, R³², R³³, R³⁴, R³⁵ R³⁶ R³⁷ R³⁸ R³⁹ R⁴⁰, R⁵⁰,R⁵¹, R⁵², R⁵³ R⁵⁴ R⁵⁴ R⁵⁶ R⁵⁷ R⁵⁸ R⁵⁹ R⁶⁰. For example, when any of Rgroups are, or contain for example through substitution, methyl, ethyl,or methoxy, the alkyl residue may be deuterated (in non-limitingembodiments, CD₃, CH₂CD₃, CD₂CD₃, CDH₂, CD₂H, CD₃, CHDCH₂D, CH₂CD₃,CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.

The compound of the present invention may form a solvate with a solvent(including water). Therefore, in one embodiment, the invention includesa solvated form of the active compound. The term “solvate” refers to amolecular complex of a compound of the present invention (includingsalts thereof) with one or more solvent molecules. Examples of solventsare water, ethanol, dimethyl sulfoxide, acetone and other common organicsolvents. The term “hydrate” refers to a molecular complex comprising acompound of the invention and water. Pharmaceutically acceptablesolvates in accordance with the invention include those wherein thesolvent may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.A solvate can be in a liquid or solid form.

A dash (“-”) is defined by context and can in addition to its literarymeaning indicate a point of attachment for a substituent. For example,—(C═O)NH₂ is attached through carbon of the keto (C═O) group. A dash(“-”) can also indicate a bond within a chemical structure. For example—C(O)—NH₂ is attached through carbon of the keto group which is bound toan amino group (NH₂).

An equal sign (“=”) is defined by context and can in addition to itsliterary meaning indicate a point of attachment for a substituentwherein the attachment is through a double bond. For example, ═CH₂represents a fragment that is doubly bonded to the parent structure andconsists of one carbon with two hydrogens bonded in a terminal fashion.═CHCH₃ on the other hand represents a fragment that is doubly bonded tothe parent structure and consists of two carbons. In the above exampleit should be noted that the stereoisomer is not delineated and that boththe cis and trans isomer are independently represented by the group.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a moietyselected from the indicated group, provided that the designated atom'snormal valence is not exceeded. For example, when the substituent is oxo(i.e., ═O), then in one embodiment, two hydrogens on the atom arereplaced. When an oxo group replaces two hydrogens in an aromaticmoiety, the corresponding partially unsaturated ring replaces thearomatic ring. For example a pyridyl group substituted by oxo is apyridone. Combinations of substituents and/or variables are permissibleonly if such combinations result in stable compounds or useful syntheticintermediates.

A stable compound or stable structure refers to a compound with a longenough residence time to either be used as a synthetic intermediate oras a therapeutic agent, as relevant in context.

“Alkyl” is a straight chain saturated aliphatic hydrocarbon group. Incertain embodiments, the alkyl is C₁-C₂, C₁-C₃, C₁-C₆, or C₁-C₃₀ (i.e.,the alkyl chain can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30carbons in length). The specified ranges as used herein indicate analkyl group with length of each member of the range described as anindependent species. For example, the term C₁-C₆ alkyl as used hereinindicates a straight alkyl group having from 1, 2, 3, 4, 5, or 6 carbonatoms and is intended to mean that each of these is described as anindependent species. For example, the term C₁-C₄alkyl as used hereinindicates a straight or branched alkyl group having from 1, 2, 3, or 4carbon atoms and is intended to mean that each of these is described asan independent species. When C₀-C_(n) alkyl is used herein inconjunction with another group, for example, (C₃-C₇cycloalkyl)C₀-C₄alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl), the indicated group, in thiscase cycloalkyl, is either directly bound by a single covalent bond(C₀alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4carbon atoms. Alkyls can also be attached via other groups such asheteroatoms as in —O—C₀-C₄alkyl(C₃-C₇cycloalkyl). Alkyls can be furthersubstituted with alkyl to make branched alkyls. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl,neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutaneand 2,3-dimethylbutane. In one embodiment, the alkyl group is optionallysubstituted as described above.

“Alkenyl” is a straight chain aliphatic hydrocarbon group having one ormore carbon-carbon double bonds each of which is independently eithercis or trans that may occur at a stable point along the chain. In oneembodiment, the double bond in a long chain similar to a fatty acid hasthe stereochemistry as commonly found in nature. Non-limiting examplesare C₂-C₃₀alkenyl, C₁₀-C₃₀alkenyl (i.e., having 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, or 30 carbons), and C₂-C₄alkenyl. The specified ranges as usedherein indicate an alkenyl group having each member of the rangedescribed as an independent species, as described above for the alkylmoiety. Examples of alkenyl include, but are not limited to, ethenyl andpropenyl. Alkenyls can be further substituted with alkyl to makebranched alkenyls. In one embodiment, the alkenyl group is optionallysubstituted as described above.

“Alkynyl” is a straight chain aliphatic hydrocarbon group having one ormore carbon-carbon triple bonds that may occur at any stable point alongthe chain, for example, C₂-C₈alkynyl or C₁₀-C₃₀alkynyl (i.e., having 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, or 30 carbons). The specified ranges as usedherein indicate an alkynyl group having each member of the rangedescribed as an independent species, as described above for the alkylmoiety. Alkynyls can be further substituted with alkyl to make branchedalkynyls. Examples of alkynyl include, but are not limited to, ethynyl,propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and5-hexynyl. In one embodiment, the alkynyl group is optionallysubstituted as described above.

“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example,can be a 1 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicatednumber of carbon atoms, for example C₁-C₄alkylene, C₁-C₃alkylene, orC₁-C₂alkylene.

“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbondouble bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkenylene.

“Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbontriple bond.

Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbonmoiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkynylene.

“Alkenylalkynyl” in one embodiment is a bivalent hydrocarbon having atleast one carbon-carbon double bond and at least one carbon-carbontriple bond. It will be recognized to one skilled in the art that thebivalent hydrocarbon will not result in hypervalency, for example,hydrocarbons that include —C═C≡C—C or —C≡C≡C—C, and must be stable.Alkenylalkynyls, for example, can be a 4 to 8 carbon moiety, 4 to 6carbon moiety, or an indicated number of carbon atoms, for exampleC₄-C₆alkenylalkynyls.

“Alkoxy” is an alkyl group as defined above covalently bound through anoxygen bridge (—O—). Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy,n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy,2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a“thioalkyl” group is an alkyl group as defined above with the indicatednumber of carbon atoms covalently bound through a sulfur bridge (—S—).In one embodiment, the alkoxy group is optionally substituted asdescribed above.

“Alkenyloxy” is an alkenyl group as defined covalently bound to thegroup it substitutes by an oxygen bridge (—O—).

“Amide” or “carboxamide” is —C(O)NR^(a)R^(b) wherein R^(a) and R^(b) areeach independently selected from hydrogen, alkyl, for example,C₁-C₆alkyl, alkenyl, for example, C₂-C₆alkenyl, alkynyl, for example,C₂-C₆alkynyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), —C₀-C₄alkyl(aryl), and—C₀-C₄alkyl(heteroaryl); or together with the nitrogen to which they arebonded, R^(a) and R^(b) can form a C₃-C₇heterocyclic ring. In oneembodiment, the R^(a) and R^(b) groups are each independently optionallysubstituted as described above.

“Carbocyclic group”, “carbocyclic ring”, or “cycloalkyl” is a saturatedor partially unsaturated (i.e., not aromatic) group containing allcarbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.Cycloalkyl substituents may be pendant from a substituted nitrogen orcarbon atom, or a substituted carbon atom that may have two substituentscan have a cycloalkyl group, which is attached as a spiro group.Examples of carbocyclic rings include cyclohexenyl, cyclohexyl,cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropylrings. In one embodiment, the carbocyclic ring is optionally substitutedas described above. In one embodiment, the cycloalkyl is a partiallyunsaturated (i.e., not aromatic) group containing all carbon ring atoms.In another embodiment, the cycloalkyl is a saturated group containingall carbon ring atoms. In another embodiment, a carbocyclic ringcomprises a caged carbocyclic group. In one embodiment, a carbocyclicring comprises a bridged carbocyclic group. An example of a cagedcarbocyclic group is adamantane. An example of a bridged carbocyclicgroup includes bicyclo[2.2.1]heptane (norbornane). In one embodiment,the caged carbocyclic group is optionally substituted as describedabove. In one embodiment, the bridged carbocyclic group is optionallysubstituted as described above.

“Hydroxyalkyl” is an alkyl group as previously described, substitutedwith at least one hydroxyl substituent.

“Halo” or “halogen” indicates independently any of fluoro, chloro,bromo, and iodo.

“Aryl” indicates aromatic groups containing only carbon in the aromaticring or rings. In one embodiment, the aryl groups contain 1 to 3separate or fused rings and is 6 to about 14 or 18 ring atoms, withoutheteroatoms as ring members. When indicated, such aryl groups may befurther substituted with carbon or non-carbon atoms or groups. Suchsubstitution may include fusion to a 4 to 7-membered saturated cyclicgroup that optionally contains 1 or 2 heteroatoms independently chosenfrom N, O, B, and S, to form, for example, a 3,4-methylenedioxyphenylgroup. Aryl groups include, for example, phenyl and naphthyl, including1-naphthyl and 2-naphthyl. In one embodiment, aryl groups are pendant.An example of a pendant ring is a phenyl group substituted with a phenylgroup. In one embodiment, the aryl group is optionally substituted asdescribed above. In one embodiment, aryl groups include, for example,dihydroindole, dihydrobenzofuran, isoindoline-1-one and indolin-2-onethat can be optionally substituted.

The term “heterocycle,” or “heterocyclic ring” as used herein refers toa saturated or a partially unsaturated (i.e., having one or more doubleand/or triple bonds within the ring without aromaticity) carbocyclicradical of 3 to about 12, and more typically 3, 5, 6, 7 to 10 ring atomsin which at least one ring atom is a heteroatom selected from nitrogen,oxygen, phosphorus, silicon, boron and sulfur, the remaining ring atomsbeing C, where one or more ring atoms is optionally substitutedindependently with one or more substituents described above. Aheterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbonatoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicyclehaving 5 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatomsselected from N, O, P, and S), for example: a bicyclo [4,5], [5,5],[5,6], or [6,6] system. In one embodiment, the only heteroatom isnitrogen. In one embodiment, the only heteroatom is oxygen. In oneembodiment, the only heteroatom is sulfur. Heterocycles are described inPaquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A.Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (JohnWiley & Sons, New York, 1950 to present), in particular Volumes 13, 14,16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. Spiro moieties arealso included within the scope of this definition. Examples of aheterocyclic group wherein 1 or 2 ring carbon atoms are substituted withoxo (═O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. Theheterocycle groups herein are optionally substituted independently withone or more substituents described herein.

“Heteroaryl” indicates a stable monocyclic aromatic ring which containsfrom 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen fromN, O, and S, with remaining ring atoms being carbon, or a stablebicyclic or tricyclic system containing at least one 5- to 7-memberedaromatic ring which contains from 1, 2, 3, or 4, or in some embodimentsfrom 1 or 2, heteroatoms chosen from N, O, B, and S, with remaining ringatoms being carbon. In one embodiment, the only heteroatom is nitrogen.In one embodiment, the only heteroatom is oxygen. In one embodiment, theonly heteroatom is sulfur. Monocyclic heteroaryl groups typically havefrom 5 to 7 ring atoms. In some embodiments bicyclic heteroaryl groupsare 9- to 10-membered heteroaryl groups, that is, groups containing 9 or10 ring atoms in which one 5- to 7-member aromatic ring is fused to asecond aromatic or non-aromatic ring. When the total number of S and Oatoms in the heteroaryl group exceeds 1, these heteroatoms are notadjacent to one another. In one embodiment, the total number of S and Oatoms in the heteroaryl group is not more than 2. In another embodiment,the total number of S and O atoms in the aromatic heterocycle is notmore than 1. Heteroaryl groups are optionally substituted independentlywith one or more substituents described herein.

“Heterocycloalkyl” is a saturated ring group. It may have, for example,1, 2, 3, or 4 heteroatoms independently chosen from N, S, and O, withremaining ring atoms being carbon. In a typical embodiment, nitrogen isthe heteroatom. Monocyclic heterocycloalkyl groups typically have from 3to about 8 ring atoms or from 4 to 6 ring atoms. Examples ofheterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl,and pyrrolinyl.

The term “esterase” refers to an enzyme that catalyzes the hydrolysis ofan ester. As used herein, the esterase can catalyze the hydrolysis ofprostaglandins described herein. In certain instances, the esteraseincludes an enzyme that can catalyze the hydrolysis of amide bonds ofprostaglandins.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

A “pharmaceutical composition” is a composition comprising at least oneactive agent, such as a compound or salt of Formula I, Formula II,Formula II′, Formula III, Formula IV, Formula V, Formula VI, FormulaIII′, Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′,Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, FormulaXIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,Formula XX, Formula XXI, Formula XXII, or Formula XXIII, and at leastone other substance, such as a pharmaceutically acceptable carrier.“Pharmaceutical combinations” are combinations of at least two activeagents which may be combined in a single dosage form or providedtogether in separate dosage forms with instructions that the activeagents are to be used together to treat any disorder described herein.

A “pharmaceutically acceptable salt” includes a derivative of thedisclosed compound in which the parent compound is modified by makinginorganic and organic, non-toxic, acid or base addition salts thereof.The salts of the present compounds can be synthesized from a parentcompound that contains a basic or acidic moiety by conventional chemicalmethods. Generally, such salt can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or thelike), or by reacting a free base form of the compound with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are typical, where practicable.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Lists of additionalsuitable salts may be found, e.g., in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418(1985).

The term “carrier” refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “patient” or “host” or “subject” is typically a human, however, may bemore generally a mammal. In an alternative embodiment it can refer tofor example, a cow, sheep, goat, horses, dog, cat, rabbit, rat, mice,fish, bird and the like.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug. As used herein, the term“parent drug” means the active form of the compounds that renders thebiological effect to treat any of the disorders described herein, or tocontrol or improve the underlying cause or symptoms associated with anyphysiological or pathological disorder described herein in a host,typically a human. Prodrugs can be used to achieve any desired effect,including to enhance properties of the parent drug or to improve thepharmaceutic or pharmacokinetic properties of the parent. Prodrugstrategies exist which provide choices in modulating the conditions forin vivo generation of the parent drug, all of which are deemed includedherein. Non-limiting examples of prodrug strategies include covalentattachment of removable groups, or removable portions of groups, forexample, but not limited to acylation, phosphorylation, phosphonylation,phosphoramidate derivatives, amidation, reduction, oxidation,esterification, alkylation, other carboxy derivatives, sulfoxy orsulfone derivatives, carbonylation or anhydride, among others. Incertain aspects of the present invention, at least one hydrophobic groupis covalently bound to the parent drug to slow release of the parentdrug in vivo.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a patient, to provide a therapeutic benefit such asan amelioration of symptoms of the selected disorder, typically anocular disorder In certain aspects, the disorder is glaucoma, a disordermediated by carbonic anhydrase, a disorder or abnormality related to anincrease in intraocular pressure (IOP), a disorder mediated by nitricoxide synthase (NOS), a disorder requiring neuroprotection such as toregenerate/repair optic nerves, allergic conjunctivitis, anterioruveitis, cataracts, dry or wet age-related macular degeneration (AMD) ordiabetic retinopathy.

“y-linolenic acid” is gamma-linolenic acid.

The term “polymer” as used herein includes oligomers.

II. Detailed Description of the Active Compounds

According to the present invention, compounds of Formula I, Formula II,Formula II′, Formula III, Formula IV, Formula V, Formula VI, FormulaIII′, Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′,Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, FormulaXIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,Formula XX, Formula XXI, Formula XXII, or Formula XXIII are provided:

as well as the pharmaceutically acceptable salts and compositionsthereof. Formula I and Formula II can be considered a prostaglandincovalently bound to a hydrophobic moiety through an ester linkage thatmay be metabolized in the eye to afford the parent prostaglandin.Formula III can be considered Brinzolamide covalently bound to ahydrophobic moiety through an N-sulfonyl aldimine or ketimine linkagethat may be metabolized in the eye to afford Brinzolamide. Formula IVcan be considered Dorzolamide covalently bound to a hydrophobic moietythrough an N-sulfonyl aldimine or ketimine linkage that may bemetabolized in the eye to afford Dorzolamide. Formula V can beconsidered Acetazolamide covalently bound to a hydrophobic moietythrough an N-sulfonyl aldimine or ketimine linkage that may bemetabolized in the eye to afford Acetazolamide. Formula VI can beconsidered Methazolamide covalently bound to a hydrophobic moietythrough an N-sulfonyl aldimine or ketimine linkage that may bemetabolized in the eye to afford Methazolamide. Formula VII can beconsidered a prostaglandin covalently bound to a carbonic anhydraseinhibitor through either a direct bond or a connecting fragment bound toboth species that may be metabolized in the eye to afford the parentprostaglandin and a carbonic anhydrase inhibitor. Formula VIII can beconsidered a derivative of Sunitinib covalently bound to either aprostaglandin or a carbonic anhydrase inhibitor through an ester orN-sulfonyl aldimine/ketimine linkage respectively that may bemetabolized in the eye to afford the parent Sunitinib derivative as wellas either a prostaglandin or a carbonic anhydrase inhibitor. Formula IXcan be considered Crizotinib covalently bound to a hydrophobic moietythrough an amide bond that may be metabolized in the eye to releaseCrizotinib. Formula X can be considered KW-2449 covalently bound to ahydrophobic moiety through an amide bond that may be metabolized in theeye to release KW-2449. Formula XI can be considered an active DLKinhibitor covalently bound to a hydrophobic moiety through an amide bondthat may be metabolized in the eye to release the active DLK inhibitor.Formula XII can be considered a derivative of Tozasertib covalentlybound to a hydrophobic moiety through an amide bond that may bemetabolized in the eye to release Tozasertib. In one embodiment, thecompound is a treatment for glaucoma, and therefore can be used as aneffective amount to treat a host in need of glaucoma treatment. Inanother embodiment, the compound acts through a mechanism other thanthose associated with glaucoma to treat a disorder described herein in ahost, typically a human.

The compounds, as described herein, may include, for example, prodrugs,which are hydrolysable to form the active carboxylic acid compound.Thus, when a compound of Formula I or Formula II is administered to amammalian subject, typically a human, the ester modifications may becleaved to release the parent free acid compound of Formula XIII.

The compounds, as described herein, may include, for example, prodrugs,which are hydrolysable to form the active sulfonamide compound. Thuswhen a compound of Formula III Formula IV, Formula V, or Formula VI isadministered to a mammalian subject, typically a human, the aldimine orketimine modifications may be cleaved to release Brinzolamide,Dorzolamide, Acetazolamide, or Methazolamide respectively.

The compounds, as described herein, may include, for example, prodrugs,which are hydrolysable to form the active sulfonamide and carboxylicacid compound. Thus when a compound of Formula VII is administered to amammalian subject, typically a human, the prodrug may be cleaved torelease the parent compounds of Formula XIII and Brinzolamide orDorzolamide or Acetazolamide, or Methazolamide.

The compounds, as described herein, may include, for example, prodrugs,which are hydrolysable to form the active Sunitinib derivative and anactive carboxylic acid or an active sulfonamide compound. Thus when acompound of Formula VIII is administered to a mammalian subject,typically a human, the prodrug may be cleaved to release the parentSunitinib derivative and a compound of Formula XIII, or Brinzolamide, orDorzolamide, or Acetazolamide, or Methazolamide. The active Sunitinibderivative is a phenol compound that has been demonstrated in theliterature to be an active RTKI (Kuchar, M., et al. (2012).“Radioiodinated Sunitinib as a potential radiotracer for imagingangiogenesis-radiosynthesis and first radiopharmacological evaluation of5-[125I]Iodo-Sunitinib.” Bioorg Med Chem Lett 22(8): 2850-2855.

The compounds, as described herein, may include, for example, prodrugs,which are hydrolysable to release the active DLK inhibitor. Thus when acompound of Formula IX, Formula X, Formula XI, or Formula XII isadministered to a mammalian subject, typically a human, the amide bondmay be cleaved to release Crizotinib, KW-2449, a piperidino DLKinhibitor, or a Tozasertib derivative respectively.

The amides and esters of commercial prostaglandins are believed to actas prodrugs in the eye, in that the ester or amide form, is hydrolyzedby an endogenous ocular enzyme, releasing the parent compound as a freeacid which is the active pharmacologic agent. However, this alsoreleases a potentially toxic and potentially irritating small aliphaticalcohol, for example, isobutanol into the eye. While effective inreducing intraocular pressure, most drugs currently in use, includinglatanoprost, bimatoprost, travoprost, may cause a significant level ofeye irritation in some patients.

In addition to the foregoing, the isopropyl esters of prostaglandins,for example, latanoprost and fluprostenol, are highly viscous, glassyoils, which can be difficult to handle and to formulate into ophthalmicsolutions. In addition, these compounds can be prone to the retention ofpotentially toxic process solvents. The higher alkyl esters or amides ofprostaglandins can be easier to handle and may not release as irritatingof an alcohol or amine upon hydrolysis.

In addition to the irritation caused by the prostaglandins themselves,and particularly the naturally-occurring and synthetic prostaglandins ofthe type presently on the market, the preservatives typically used inophthalmic solutions are known to potentially irritate a percentage ofthe population. Thus, despite the fact that the prostaglandins representan important class of potent therapeutic agents for the treatment ofglaucoma, the unwanted side effects of these drugs, particularly ocularirritation and inflammation, may limit patient use and can be related topatient withdrawal from the use of these drugs. The higher alkyl estersand amides of prostaglandins as disclosed herein, can be less irritatingto patients yet therapeutically effective.

Non-limiting examples of compounds falling Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, with variations inthe variables e.g., L¹, L², R¹-R²⁷, and A, are illustrated below. Thedisclosure includes all combinations of these definitions so long as astable compound results.

III. Pharmaceutical Preparations

One embodiment provides compositions including the compounds describedherein. In certain embodiments, the composition includes a compound ofFormula I, Formula II, Formula II′, Formula III, Formula IV, Formula V,Formula VI, Formula III′, Formula IV′, Formula V′, Formula VI′, FormulaVII, Formula VII′, Formula VIII, Formula IX, Formula X, Formula XI,Formula XII, Formula XIV, Formula XV, Formula XVI, Formula XVII, FormulaXVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, or FormulaXXIII in combination with a pharmaceutically acceptable carrier,excipient or diluent. In one embodiment, the composition is apharmaceutical composition for treating an eye disorder or eye disease.Non-limiting exemplary eye disorder or disease treatable with thecomposition includes age related macular degeneration, alkaline erosivekeratoconjunctivitis, allergic conjunctivitis, allergic keratitis,anterior uveitis, Behcet's disease, blepharitis, blood-aqueous barrierdisruption, chorioiditis, chronic uveitis, conjunctivitis, contactlens-induced keratoconjunctivitis, corneal abrasion, corneal trauma,corneal ulcer, crystalline retinopathy, cystoid macular edema,dacryocystitis, diabetic keratophathy, diabetic macular edema, diabeticretinopathy, dry eye disease, dry age-related macular degeneration,eosinophilic granuloma, episcleritis, exudative macular edema, Fuchs'Dystrophy, giant cell arteritis, giant papillary conjunctivitis,glaucoma, glaucoma surgery failure, graft rejection, herpes zoster,inflammation after cataract surgery, iridocorneal endothelial syndrome,iritis, keratoconjunctiva sicca, keratoconjunctival inflammatorydisease, keratoconus, lattice dystrophy, map-dot-fingerprint dystrophy,necrotic keratitis, neovascular diseases involving the retina, uvealtract or cornea, for example, neovascular glaucoma, cornealneovascularization, neovascularization resulting following a combinedvitrectomy and lensectomy, neovascularization of the optic nerve, andneovascularization due to penetration of the eye or contusive ocularinjury, neuroparalytic keratitis, non-infectious uveitisocular herpes,ocular lymphoma, ocular rosacea, ophthalmic infections, ophthalmicpemphigoid, optic neuritis, panuveitis, papillitis, pars planitis,persistent macular edema, phacoanaphylaxis, posterior uveitis,post-operative inflammation, proliferative diabetic retinopathy,proliferative sickle cell retinopathy, proliferative vitreoretinopathy,retinal artery occlusion, retinal detachment, retinal vein occlusion,retinitis pigmentosa, retinopathy of prematurity, rubeosis iritis,scleritis, Stevens-Johnson syndrome, sympathetic ophthalmia, temporalarteritis, thyroid associated ophthalmopathy, uveitis, vernalconjunctivitis, vitamin A insufficiency-induced keratomalacia,vitreitis, and wet age-related macular degeneration.

Compounds of Formula I, Formula II, Formula II′, Formula III, FormulaIV, Formula V, Formula VI, Formula III′, Formula IV′, Formula V′,Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula IX,Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, FormulaXVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,Formula XXII, or Formula XXIII or its salt, can be delivered by anymethod known for ocular delivery. Methods include but are not limited toconventional (solution, suspension, emulsion, ointment, inserts andgels); vesicular (liposomes, niosomes, discomes and pharmacosomes),particulates (microparticles and nanoparticles), advanced materials(scleral plugs, gene delivery, siRNA and stem cells); and controlledrelease systems (implants, hydrogels, dendrimeres, iontoporesis,collagen shields, polymeric solutions, therapeutic contact lenses,cyclodextrin carriers, microneedles and microemulsions).

In certain aspects, a delivery system is used including but not limitedto the following; i) a degradable polymeric composition; ii) anon-degradable polymeric composition; (iii) a hydrogel; (iv) a depot;(v) a particle containing a core; vi) a surface-coated particle; vii) amulti-layered polymeric or non-polymeric or mixed polymeric andnon-polymeric particle; viii) a polymer blend and/or ix) a particle witha coating on the surface of the particle. The polymers can include, forexample, hydrophobic regions. In some embodiments, at least about 30, 40or 50% of the hydrophobic regions in the coating molecules have amolecular mass of least about 2 kDa. In some embodiments, at least about30, 40 or 50% of the hydrophobic regions in the coating molecules have amolecular mass of least about 3 kDa. In some embodiments, at least about30, 40 or 50% of the hydrophobic regions in the coating molecules have amolecular mass of least about 4 kDa. In some embodiments, at least about30, 40 or 50% of the hydrophobic regions in the coating molecules have amolecular mass of least about 5 kDa. In certain embodiments, up to 5,10, 20, 30, 40, 50, 60, 70, 80, 90 or even 95% or more of a copolymer orpolymer blend consists of a hydrophobic polymer or polymer segment. Insome embodiments, the polymeric material includes up to 2, 3, 4, 5, 6,7, 8, 9, or 10% or more hydrophilic polymer. In one embodiment, thehydrophobic polymer is a polymer or copolymer of lactic acid or glycolicacid, including PLGA. In one embodiment, the hydrophilic polymer ispolyethylene glycol. In certain embodiments a triblock polymer such as aPluronic is used. The drug delivery system can be suitable foradministration into an eye compartment of a patient, for example byinjection into the eye compartment. In some embodiments, the coreincludes a biocompatible polymer. As used herein, unless the contextindicates otherwise, “drug delivery system”, “carrier”, and “particlecomposition” can all be used interchangeably. In a typical embodimentthis delivery system is used for ocular delivery.

The particle in the drug delivery system can be of any desired size thatachieves the desired result. The appropriate particle size can varybased on the method of administration, the eye compartment to which thedrug delivery system is administered, the therapeutic agent employed andthe eye disorder to be treated, as will be appreciated by a person ofskill in the art in light of the teachings disclosed herein. Forexample, in some embodiments the particle has a diameter of at leastabout 1 nm, or from about 1 nm to about 50 microns. The particle canalso have a diameter of, for example, from about 1 nm to about 15, 16,17, 18, 19, 2, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 microns; or fromabout 10 nm to about less than 30, 35, 40, 45 or 50 microns; or fromabout 10 nm to about less than 28 microns; from about 1 nm to about 5microns; less than about 1 nm; from about 1 nm to about 3 microns; orfrom about 1 nm to about 1000 nm; or from about 25 nm to about 75 nm; orfrom about 20 nm to less than or about 30 nm; or from about 100 nm toabout 300 nm. In some embodiments, the average particle size can beabout up to 1 nm, 10 nm, 25 nm, 30 nm, 50 nm, 150 nm, 200 nm, 250 nm,300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm,750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, or more. In someembodiments, the particle size can be about 100 microns or less, about50 microns or less, about 30 microns or less, about 10 microns or less,about 6 microns or less, about 5 microns or less, about 3 microns orless, about 1000 nm or less, about 800 nm or less, about 600 nm or less,about 500 nm or less, about 400 nm or less, about 300 nm or less, about200 nm or less, or about 100 nm or less. In some embodiments, theparticle can be a nanoparticle or a microparticle. In some embodiments,the drug delivery system can contain a plurality of sizes particles. Theparticles can be all nanoparticles, all microparticles, or a combinationof nanoparticles and microparticles.

When delivering the active material in a polymeric delivery composition,the active material can be distributed homogeneously, heterogeneously,or in one or more polymeric layers of a multi-layered composition,including in a polymer coated core or a bare uncoated core.

In some embodiments, the drug delivery system includes a particlecomprising a core. In some embodiments a compound of Formula I, FormulaII, Formula II′, Formula III, Formula IV, Formula V, Formula VI, FormulaIII′, Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′,Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, FormulaXIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,Formula XX, Formula XXI, Formula XXII, or Formula XXIII can be presentin the core in a suitable amount, e.g., at least about 1% weight (wt),at least about 5% wt, at least about 10% wt, at least about 20% wt, atleast about 30% wt, at least about 40% wt, at least about 50% wt, atleast about 60% wt, at least about 70% wt, at least about 80% wt, atleast about 85% wt, at least about 90% wt, at least about 95% wt, or atleast about 99% wt of the core. In one embodiment, the core is formed of100% wt of the pharmaceutical agent. In some cases, the pharmaceuticalagent may be present in the core at less than or equal to about 100% wt,less than or equal to about 90% wt, less than or equal to about 80% wt,less than or equal to about 70% wt, less than or equal to about 60% wt,less than or equal to about 50% wt, less than or equal to about 40% wt,less than or equal to about 30% wt, less than or equal to about 20% wt,less than or equal to about 10% wt, less than or equal to about 5% wt,less than or equal to about 2% wt, or less than or equal to about 1% wt.Combinations of the above-referenced ranges are also possible (e.g.,present in an amount of at least about 80% wt and less than or equal toabout 100% wt). Other ranges are also possible.

In embodiments in which the core particles comprise relatively highamounts of a pharmaceutical agent (e.g., at least about 50% wt of thecore particle), the core particles generally have an increased loadingof the pharmaceutical agent compared to particles that are formed byencapsulating agents into polymeric carriers. This is an advantage fordrug delivery applications, since higher drug loadings mean that fewernumbers of particles may be needed to achieve a desired effect comparedto the use of particles containing polymeric carriers.

In some embodiments, the core is formed of a solid material having arelatively low aqueous solubility (i.e., a solubility in water,optionally with one or more buffers), and/or a relatively low solubilityin the solution in which the solid material is being coated with asurface-altering agent. For example, the solid material may have anaqueous solubility (or a solubility in a coating solution) of less thanor equal to about 5 mg/mL, less than or equal to about 2 mg/mL, lessthan or equal to about 1 mg/mL, less than or equal to about 0.5 mg/mL,less than or equal to about 0.1 mg/mL, less than or equal to about 0.05mg/mL, less than or equal to about 0.01 mg/mL, less than or equal toabout 1 ng/mL, less than or equal to about 0.1 ng/mL, less than or equalto about 0.01 ng/mL, less than or equal to about 1 ng/mL, less than orequal to about 0.1 ng/mL, or less than or equal to about 0.01 ng/mL at25° C. In some embodiments, the solid material may have an aqueoussolubility (or a solubility in a coating solution) of at least about 1pg/mL, at least about 10 pg/mL, at least about 0.1 ng/mL, at least about1 ng/mL, at least about 10 ng/mL, at least about 0.1 ng/mL, at leastabout 1 ng/mL, at least about 5 ng/mL, at least about 0.01 mg/mL, atleast about 0.05 mg/mL, at least about 0.1 mg/mL, at least about 0.5mg/mL, at least about 1.0 mg/mL, at least about 2 mg/mL. Combinations ofthe above-noted ranges are possible (e.g., an aqueous solubility or asolubility in a coating solution of at least about 10 pg/mL and lessthan or equal to about 1 mg/mL). Other ranges are also possible. Thesolid material may have these or other ranges of aqueous solubilities atany point throughout the pH range (e.g., from pH 1 to pH 14).

In some embodiments, the core may be formed of a material within one ofthe ranges of solubilities classified by the U.S. PharmacopeiaConvention: e.g., very soluble: >1,000 mg/mL; freely soluble: 100-1,000mg/mL; soluble: 33-100 mg/mL; sparingly soluble: 10-33 mg/mL; slightlysoluble: 1-10 mg/mL; very slightly soluble: 0.1-1 mg/mL; and practicallyinsoluble: <0.1 mg/mL.

Although a core may be hydrophobic or hydrophilic, in many embodimentsdescribed herein, the core is substantially hydrophobic. “Hydrophobic”and “hydrophilic” are given their ordinary meaning in the art and, aswill be understood by those skilled in the art, in many instancesherein, are relative terms. Relative hydrophobicities andhydrophilicities of materials can be determined by measuring the contactangle of a water droplet on a planar surface of the substance to bemeasured, e.g., using an instrument such as a contact angle goniometerand a packed powder of the core material.

In some embodiments, the core particles described herein may be producedby nanomilling of a solid material (e.g., a compound of Formula I,Formula II, Formula II′, Formula III, Formula IV, Formula V, Formula VI,Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII, FormulaVII′, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIII) inthe presence of one or more stabilizers/surface-altering agents. Smallparticles of a solid material may require the presence of one or morestabilizers/surface-altering agents, particularly on the surface of theparticles, in order to stabilize a suspension of particles withoutagglomeration or aggregation in a liquid solution. In some suchembodiments, the stabilizer may act as a surface-altering agent, forminga coating on the particle.

In a wet milling process, milling can be performed in a dispersion(e.g., an aqueous dispersion) containing one or more stabilizers (e.g.,a surface-altering agent), a grinding medium, a solid to be milled(e.g., a solid pharmaceutical agent), and a solvent. Any suitable amountof a stabilizer/surface-altering agent can be included in the solvent.In some embodiments, a stabilizer/surface-altering agent may be presentin the solvent in an amount of at least about 0.001% (wt or % weight tovolume (w:v)), at least about 0.01, at least about 0.1, at least about0.5, at least about 1, at least about 2, at least about 3, at leastabout 4, at least about 5, at least about 6, at least about 7, at leastabout 8, at least about 10, at least about 12, at least about 15, atleast about 20, at least about 40, at least about 60, or at least about80% of the solvent. In some cases, the stabilizer may be present in thesolvent in an amount of about 100% (e.g., in an instance where thestabilizer/surface-altering agent is the solvent). In other embodiments,the stabilizer may be present in the solvent in an amount of less thanor equal to about 100, less than or equal to about 80, less than orequal to about 60, less than or equal to about 40, less than or equal toabout 20, less than or equal to about 15, less than or equal to about12, less than or equal to about 10, less than or equal to about 8, lessthan or equal to about 7%, less than or equal to about 6%, less than orequal to about 5%, less than or equal to about 4%, less than or equal toabout 3%, less than or equal to about 2%, or less than or equal to about1% of the solvent. Combinations of the above-referenced ranges are alsopossible (e.g., an amount of less than or equal to about 5% and at leastabout 1% of the solvent). Other ranges are also possible. The particularrange chosen may influence factors that may affect the ability of theparticles to penetrate mucus such as the stability of the coating of thestabilizer/surface-altering agent on the particle surface, the averagethickness of the coating of the stabilizer/surface-altering agent on theparticles, the orientation of the stabilizer/surface-altering agent onthe particles, the density of the stabilizer/surface altering agent onthe particles, stabilizer/drug ratio, drug concentration, the size andpolydispersity of the particles formed, and the morphology of theparticles formed.

The compound of Formula I, Formula II, Formula II′, Formula III, FormulaIV, Formula V, Formula VI, Formula III′, Formula IV′, Formula V′,Formula VI′, Formula VII, Formula VII′, Formula VIII, Formula IX,Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, FormulaXVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,Formula XXII, or Formula XXIII (or salt thereof) may be present in thesolvent in any suitable amount. In some embodiments, the pharmaceuticalagent (or salt thereof) is present in an amount of at least about 0.001%(wt % or % weight to volume (w:v)), at least about 0.01%, at least about0.1%, at least about 0.5%, at least about 1%, at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about 6%,at least about 7%, at least about 8%, at least about 10%, at least about12%, at least about 15%, at least about 20%, at least about 40%, atleast about 60%, or at least about 80% of the solvent. In some cases,the pharmaceutical agent (or salt thereof) may be present in the solventin an amount of less than or equal to about 100%, less than or equal toabout 90%, less than or equal to about 80%, less than or equal to about60%, less than or equal to about 40%, less than or equal to about 20%,less than or equal to about 15%, less than or equal to about 12%, lessthan or equal to about 10%, less than or equal to about 8%, less than orequal to about 7%, less than or equal to about 6%, less than or equal toabout 5%, less than or equal to about 4%, less than or equal to about3%, less than or equal to about 2%, or less than or equal to about 1% ofthe solvent. Combinations of the above-referenced ranges are alsopossible (e.g., an amount of less than or equal to about 20% and atleast about 1% of the solvent). In some embodiments, the pharmaceuticalagent is present in the above ranges but in w:v.

The ratio of stabilizer/surface-altering agent to pharmaceutical agent(or salt thereof) in a solvent may also vary. In some embodiments, theratio of stabilizer/surface-altering agent to pharmaceutical agent (orsalt thereof) may be at least 0.001:1 (weight ratio, molar ratio, or w:vratio), at least 0.01:1, at least 0.01:1, at least 1:1, at least 2:1, atleast 3:1, at least 5:1, at least 10:1, at least 25:1, at least 50:1, atleast 100:1, or at least 500:1. In some cases, the ratio ofstabilizer/surface-altering agent to pharmaceutical agent (or saltthereof) may be less than or equal to 1000:1 (weight ratio or molarratio), less than or equal to 500:1, less than or equal to 100:1, lessthan or equal to 75:1, less than or equal to 50:1, less than or equal to25:1, less than or equal to 10:1, less than or equal to 5:1, less thanor equal to 3:1, less than or equal to 2:1, less than or equal to 1:1,or less than or equal to 0.1:1.

Combinations of the above-referenced ranges are possible (e.g., a ratioof at least 5:1 and less than or equal to 50:1). Other ranges are alsopossible.

Stabilizers/surface-altering agents may be, for example, polymers orsurfactants. Examples of polymers are those suitable for use incoatings, as described in more detail below. Non-limiting examples ofsurfactants include L-a-phosphatidylcholine (PC),1,2-dipalmitoylphosphatidycholine (DPPC), oleic acid, sorbitantrioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylenesorbitan monolaurate, polyoxyethylene sorbitan monooleate, naturallecithin, oleyl polyoxyethylene ether, stearyl polyoxyethylene ether,lauryl polyoxyethylene ether, block copolymers of oxyethylene andoxypropylene, synthetic lecithin, diethylene glycol dioleate,tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glycerylmonooleate, glyceryl monostearate, glyceryl monoricinoleate, cetylalcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridiniumchloride, benzalkonium chloride, olive oil, glyceryl monolaurate, cornoil, cotton seed oil, and sunflower seed oil. Derivatives of theabove-noted compounds are also possible. Combinations of the above-notedcompounds and others described herein may also be used assurface-altering agents in the inventive particles. As described herein,in some embodiments a surface-altering agent may act as a stabilizer, asurfactant, and/or an emulsifier. In some embodiments, the surfacealtering agent may aid particle transport in mucus.

It should be appreciated that while in some embodiments the stabilizerused for milling forms a coating on a particle surface, which coatingrenders particle mucus penetrating, in other embodiments, the stabilizermay be exchanged with one or more other surface-altering agents afterthe particle has been formed. For example, in one set of methods, afirst stabilizer/surface-altering agent may be used during a millingprocess and may coat a surface of a core particle, and then all orportions of the first stabilizer/surface-altering agent may be exchangedwith a second stabilizer/surface-altering agent to coat all or portionsof the core particle surface. In some cases, the secondstabilizer/surface-altering agent may render the particle mucuspenetrating more than the first stabilizer/surface-altering agent. Insome embodiments, a core particle having a coating including multiplesurface-altering agents may be formed.

In other embodiments, core particles may be formed by a precipitationtechnique. Precipitation techniques (e.g., microprecipitationtechniques, nanoprecipitation techniques) may involve forming a firstsolution comprising a compound of Formula I, Formula II, Formula II′,Formula III, Formula IV, Formula V, Formula VI, Formula III′, FormulaIV′, Formula V′, Formula VI′, Formula VII, Formula VII′, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV,Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX,Formula XXI, Formula XXII, or Formula XXIII and a solvent, wherein thematerial is substantially soluble in the solvent. The solution may beadded to a second solution comprising another solvent in which thematerial is substantially insoluble, thereby forming a plurality ofparticles comprising the material. In some cases, one or moresurface-altering agents, surfactants, materials, and/or bioactive agentsmay be present in the first and/or second solutions. A coating may beformed during the process of precipitating the core (e.g., theprecipitating and coating steps may be performed substantiallysimultaneously). In other embodiments, the particles are first formedusing a precipitation technique, following by coating of the particleswith a surface-altering agent.

In some embodiments, a precipitation technique may be used to formparticles (e.g., nanocrystals) of a salt of a compound of Formula I,Formula II, Formula II′, Formula III, Formula IV, Formula V, Formula VI,Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII, FormulaVII′, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,Formula XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIII.Generally, a precipitation technique involves dissolving the material tobe used as the core in a solvent, which is then added to a miscibleanti-solvent with or without excipients to form the core particle. Thistechnique may be useful for preparing particles of pharmaceutical agentsthat are soluble in aqueous solutions (e.g., agents having a relativelyhigh aqueous solubility). In some embodiments, pharmaceutical agentshaving one or more charged or ionizable groups can interact with acounter ion (e.g., a cation or an anion) to form a salt complex.

As described herein, in some embodiments, a method of forming a coreparticle involves choosing a stabilizer that is suitable for bothnanomilling and for forming a coating on the particle and rendering theparticle mucus penetrating. For example, as described in more detailbelow, it has been demonstrated that 200-500 nm nanoparticles of a modelcompound pyrene produced by nanomilling of pyrene in the presence ofPluronic® F127 resulted in particles that can penetrate physiologicalmucus samples at the same rate as well-established polymer-based MPP.Interestingly, it was observed that only a handful ofstabilizers/surface-altering agents tested fit the criteria of beingsuitable for both nanomilling and for forming a coating on the particlethat renders the particle mucus penetrating, as described in more detailbelow.

IV. Description of Polymeric Delivery Materials

The particles of the drug delivery system can include a biocompatiblepolymer. As used herein, the term “biocompatible polymer” encompassesany polymer than can be administered to a patient without anunacceptable adverse effects to the patient.

Examples of biocompatible polymers include but are not limited topolystyrenes; poly(hydroxy acid); poly(lactic acid); poly(glycolicacid); poly(lactic acid-co-glycolic acid); poly(lactic-co-glycolicacid); poly(lactide); poly(glycolide); poly(lactide-co-glycolide);polyanhydrides; polyorthoesters; polyamides; polycarbonates;polyalkylenes; polyethylenes; polypropylene; polyalkylene glycols;poly(ethylene glycol); polyalkylene oxides; poly(ethylene oxides);polyalkylene terephthalates; poly(ethylene terephthalate); polyvinylalcohols; polyvinyl ethers; polyvinyl esters; polyvinyl halides;poly(vinyl chloride); polyvinylpyrrolidone; polysiloxanes; poly(vinylalcohols); poly(vinyl acetate); polyurethanes; co-polymers ofpolyurethanes; derivativized celluloses; alkyl cellulose; hydroxyalkylcelluloses; cellulose ethers; cellulose esters; nitro celluloses; methylcellulose; ethyl cellulose; hydroxypropyl cellulose; hydroxy-propylmethyl cellulose; hydroxybutyl methyl cellulose; cellulose acetate;cellulose propionate; cellulose acetate butyrate; cellulose acetatephthalate; carboxylethyl cellulose; cellulose triacetate; cellulosesulfate sodium salt; polymers of acrylic acid; methacrylic acid;copolymers of methacrylic acid; derivatives of methacrylic acid;poly(methyl methacrylate); poly(ethyl methacrylate);poly(butylmethacrylate); poly(isobutyl methacrylate);poly(hexylmethacrylate); poly(isodecyl methacrylate); poly(laurylmethacrylate); poly(phenyl methacrylate); poly(methyl acrylate);poly(isopropyl acrylate); poly(isobutyl acrylate); poly(octadecylacrylate); poly(butyric acid); poly(valeric acid);poly(lactide-co-caprolactone); copolymers ofpoly(lactide-co-caprolactone); blends of poly(lactide-co-caprolactone);hydroxyethyl methacrylate (HEMA); copolymers of HEMA with acrylate;copolymers of HEMA with polymethylmethacrylate (PMMA);polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA); acrylatepolymers/copolymers; acrylate/carboxyl polymers; acrylate hydroxyland/or carboxyl copolymers; polycarbonate-urethane polymers;silicone-urethane polymers; epoxy polymers; cellulose nitrates;polytetramethylene ether glycol urethane;polymethylmethacrylate-2-hydroxyethylmethacrylate copolymer;polyethylmethacrylate-2-hydroxyethylmethacrylate copolymer;polypropylmethacrylate-2-hydroxyethylmethacrylate copolymer;polybutylmethacrylate-2-hydroxyethylmethacrylate copolymer;polymethylacrylate-2-hydroxyethylmethacrylate copolymer;polyethylacrylate-2-hydroxyethylmethacrylate copolymer;polypropylacrylate-2-hydroxymethacrylate copolymer;polybutylacrylate-2-hydroxyethylmethacrylate copolymer;copolymermethylvinylether maleicanhydride copolymer; poly(2-hydroxyethyl methacrylate) polymer/copolymer; acrylate carboxyland/or hydroxy copolymer; olefin acrylic acid copolymer; ethyleneacrylic acid copolymer; polyamide polymers/copolymers; polyimidepolymers/copolymers; ethylene vinylacetate copolymer; polycarbonateurethane; silicone urethane; polyvinylpyridine copolymers; polyethersulfones; polygalactin, poly-(isobutyl cyanoacrylate), andpoly(2-hydroxyethyl-L-glutamine); polydimethyl siloxane;poly(caprolactones); poly(ortho esters); polyamines; polyethers;polyesters; polycarbamates; polyureas; polyimides; polysulfones;polyacetylenes; polyethyeneimines; polyisocyanates; polyacrylates;polymethacrylates; polyacrylonitriles; polyarylates; and combinations,copolymers and/or mixtures of two or more of any of the foregoing. Insome cases, the particle includes a hydrophobic material and at leastone bioactive agent. In certain embodiments, the hydrophobic material isused instead of a polymer. In other embodiments, the hydrophobicmaterial is used in addition to a polymer.

An active compound as described herein can be physically mixed in thepolymeric material, including in an interpenetrating polymer network orcan be covalently bound to the polymeric material

Linear, non-linear or linear multiblock polymers or copolymers can beused to form nanoparticles, microparticles, and implants (e.g., rods,discs, wafers, etc.) useful for the delivery to the eye. The polymerscan contain one or more hydrophobic polymer segments and one or morehydrophilic polymer segments covalently connected through a linear linkor multivalent branch point to form a non-linear multiblock copolymercontaining at least three polymeric segments. The polymer can be aconjugate further containing one or more therapeutic, prophylactic, ordiagnostic agents covalently attached to the one or more polymersegments. By employing a polymer-drug conjugate, particles can be formedwith more controlled drug loading and drug release profiles. Inaddition, the solubility of the conjugate can be controlled so as tominimize soluble drug concentration and, therefore, toxicity.

The one or more hydrophobic polymer segments, independently, can be anybiocompatible hydrophobic polymer or copolymer. In some cases, the oneor more hydrophobic polymer segments are also biodegradable. Examples ofsuitable hydrophobic polymers include polyesters such as polylacticacid, polyglycolic acid, or polycaprolactone, polyanhydrides, such aspolysebacic anhydride, and copolymers thereof. In certain embodiments,the hydrophobic polymer is a polyanhydride, such as polysebacicanhydride or a copolymer thereof. The one or more hydrophilic polymersegments can be any hydrophilic, biocompatible, non-toxic polymer orcopolymer. The hydrophilic polymer segment can be, for example, apoly(alkylene glycol), a polysaccharide, poly(vinyl alcohol),polypyrrolidone, a polyoxyethylene block copolymer (PLURONIC®) or acopolymers thereof. In preferred embodiments, the one or morehydrophilic polymer segments are, or are composed of, polyethyleneglycol (PEG).

WO 2016/100380A1 and WO 2016/100392 A1 describe certain sunitinibdelivery systems, which can also be used in the present invention todeliver sunitinib or another active agent provided by the currentinvention, and as described further herein. For example, WO2016/100380A1 and WO 2016/100392 A1 describe that a polymeric sunitinibdrug formulation can be prepared by: (i) dissolving or dispersingsunitinib or its salt in an organic solvent optionally with an alkalineagent; (ii) mixing the solution/dispersion of step (i) with a polymersolution that has a viscosity of at least about 300 cPs (or perhaps atleast about 350, 400, 500, 600, 700 or 800 or more cPs); (iii) mixingthe drug polymer solution/dispersion of step (ii) with an aqueousnon-acidic or alkaline solution (for example at least approximately a pHof 7, 8, or 9 and typically not higher than about 10) optionally with asurfactant or emulsifier, to form a solvent-laden sunitinib encapsulatedmicroparticle, (iv) isolating the microparticles. When sunitinib malateor another pharmaceutically acceptable salt of sunitinib is used, it wasreported that it may be useful to include the alkaline agent in theorganic solvent. However, when sunitinib free base is used, then it wasreported that adding an acid to the organic solvent can improve drugloading of the microparticle. Examples were provided demonstrating thatpolyesters such as PLGA, PEG-PLGA (PLA) and PEG-PLGA/PLGA blendmicroparticles display sustained release of sunitinib or its analog orpharmaceutically acceptable salt. The PCT references describe thatpolymer microparticles composed of PLGA and PEG covalently conjugated toPLGA (M_(w) 45 kDa) (PLGA45k-PEG5k) loaded with sunitinib malate wereprepared using a single emulsion solvent evaporation method. Loadingimprovement was achieved by increasing the alkalinity of sunitinibmalate in solution, up to 16.1% with PEG-PLGA, which could be furtherincreased by adding DMF, compared to only 1% with no alkaline added.Sunitinib malate loading was further increased by increasing the pH ofthe aqueous solution as well as the polymer solution. Still furthersignificant increases in sunitinib malate loading in the microparticleswas achieved by increasing polymer concentration or viscosity. It wasreported in these PCT applications that the loading of sunitinib can beincreased by increasing the alkalinity of the sunitinib in solutionduring encapsulation. This can be achieved by selection of the solvent,adding alkalizing agents to the solvent, or including alkaline drugswith the sunitinib. Examples of compounds that can be added for thispurpose include solvents or solvent additives such as dimethylacetamide(DMA), DMTA, triethylamine (TEA), aniline, ammonium, and sodiumhydroxide, drugs such as Vitamin B4, caffeine, alkaloids, nicotine, theanalgesic morphine, the antibacterial berberine, the anticancer compoundvincristine, the antihypertension agent reserpine, the cholinomimeticgalantamine, the anticholinergic agent atropine, the vasodilatorvincamine, the antiarrhythmia compound quinidine, the antiasthmatherapeutic ephedrine, and the antimalarial drug quinine. Surfactantsinclude anionic, cationic and non-ionic surfactants, such as, but notlimited to, polyvinyl alcohol, F-127, lectin, fatty acids,phospholipids, polyoxyethylene sorbitan fatty acid derivatives,tocopherols and castor oil. The PCTs also reported that drug loading inthe particle is significantly affected by the acid value. For example,raising the pH by addition of alkaline significantly increases theamount of sunitinib malate incorporated. Loading also can be increasedby changing the water phase pH. For example, when water phase (such asPBS) pH is raised from 6.8 to 7.4. Drug loading can also be increased byincreasing both polymer and drug concentration, polymer molecularweight. The preferred aqueous pH is higher than 6 and lower than 10,more for example between pH 6 and 8. According to WO 2016/100380A1 andWO 2016/100392 A1, polymer concentration and viscosity can affectencapsulation efficiency. For example, it was reported that for the sameformulation composition (99% PLGA 75:25 4 A and 1% PLGA-PEG (PEG MW 5Kd, PLGA MW˜45 Kd)) at different polymer concentrations indichloromethane (DCM), the encapsulation efficiency increases to over50% at 100 mg/mL polymer concentration. The dynamic viscosity of thispolymer solution in DCM, prior to mixing with sunitinib malate solutionin DMSO, is estimated to be around 350 cPs. The preferred minimalviscosity of polymer solution in DCM is about 350 cPs. In a preferredembodiment, the polymer concentration in DCM is 140 mg/mL, which isapproximately 720 cPs by calculation. Particles made of 99% PLGA 7525 6Eand 1% PLGA-PEG (PEG MW 5 Kd, PLGA MW˜45 Kd) can have a polymerconcentration in DCM ranging from 100-200 mg/mL. Since PLGA 7525 6E is apolymer with higher Mw than that of PLGA 7525 4 A, the polymer solutionin DCM is more viscous with a dynamic viscosity of about 830 cPs. Drugloading is also significantly affected by the method of making and thesolvent used. For example, S/O/W single emulsion method will yield ahigher loading than O/W single emulsion method even without control theacid value. In addition, W/O/W double emulsions have been shown tosignificantly improve drug loading of less hydrophobic salt forms oversingle O/W emulsions. The ratio of continuous phase to dispersed phasecan also significantly alter the encapsulation efficiency and drugloading by modulation of the rate of particle solidification. The rateof polymer solidification with the evaporation of solvent affects thedegree of porosity within microparticles. A large CP:DP ratio results infaster polymer precipitation, less porosity, and higher encapsulationefficiency and drug loading. However, decreasing the rate of evaporationof the solvent during particle preparation can also lead to improvementsin drug loading of highly polar compounds. As the organic phaseevaporates, highly polar compounds within the organic phase is driven tothe surface of the particles resulting in poor encapsulation and drugloading. By decreasing the rate of solvent evaporation by decreasing thetemperature or rate of stirring, encapsulation efficiency and % drugloading can be increased for highly polar compounds.

These technologies can be used by one of skill in the art to deliver anyof the active compounds as described generally in this specification.

U.S. Pat. No. 8,889,193 and PCT/US2011/026321 disclose, for example, amethod for treating an eye disorder in a patient in need thereof,comprising administering into the eye, for example, by intravitrealinjection into the vitreous chamber of the eye, an effective amount of adrug delivery system which comprises: (i) a microparticle including acore which includes the biodegradable polymer polylactide-co-glycolide;(ii) a coating associated with the core which is non-covalentlyassociated with the microparticle particle; wherein the coating moleculehas a hydrophilic region and a hydrophobic region, and wherein thehydrophilic region is polyethylene glycol; and (iii) a therapeuticallyeffective amount of a therapeutic agent, wherein the drug deliverysystem provides sustained release of the therapeutic agent into thevitreous chamber over a period of time of at least three months; andwherein the vitreous chamber of the eye exhibits at least 10% lessinflammation or intraocular pressure than if the particle were uncoated.In certain embodiments, the microparticle can be about 50 or 30 micronsor less. The delivery system described in U.S. Pat. No. 8,889,193 andPCT/US2011/026321 can be used to deliver any of the active agentsdescribed herein.

In some embodiments, the drug delivery systems contain a particle with acoating on the surface, wherein the coating molecules have hydrophilicregions and, optionally, hydrophobic regions,

The drug delivery system can include a coating. The coating can bedisposed on the surface of the particle, for example by bonding,adsorption or by complexation. The coating can also be intermingled ordispersed within the particle as well as disposed on the surface of theparticle.

The homogeneous or heterogenous polymer or polymeric coating can be, forexample, polyethylene glycol, polyvinyl alcohol (PVA), or similarsubstances. The coating can be, for example, vitamin E-PEG 1k or vitaminE-PEG 5k or the like. Vitamin E-PEG 5k can help present a dense coatingof PEG on the surface of a particle. The coating can also includenonionic surfactants such as those composed of polyalkylene oxide, e.g.,polyoxyethylene (PEO), also referred to herein as polyethylene glycol;or polyoxypropylene (PPO), also referred to herein as polypropyleneglycol (PPG), and can include a copolymer of more than one alkyleneoxide.

The polymer or copolymer can be, for example, a random copolymer, analternating copolymer, a block copolymer or graft copolymer.

In some embodiments, the coating can include apolyoxyethylene-polyoxypropylene copolymer, e.g., block copolymer ofethylene oxide and propylene oxide. (i.e., poloxamers). Examples ofpoloxamers suitable for use in the present invention include, forexample, poloxamers 188, 237, 338 and 407. These poloxamers areavailable under the trade name Pluronic® (available from BASF, MountOlive, N.J.) and correspond to Pluronic® F-68, F-87, F-108 and F-127,respectively. Poloxamer 188 (corresponding to Pluronic® F-68) is a blockcopolymer with an average molecular mass of about 7,000 to about 10,000Da, or about 8,000 to about 9,000 Da, or about 8,400 Da. Poloxamer 237(corresponding to Pluronic® F-87) is a block copolymer with an averagemolecular mass of about 6,000 to about 9,000 Da, or about 6,500 to about8,000 Da, or about 7,7000 Da. Poloxamer 338 (corresponding to Pluronic®F-108) is a block copolymer with an average molecular mass of about12,000 to about 18,000 Da, or about 13,000 to about 15,000 Da, or about14,600 Da. Poloxamer 407 (corresponding to Pluronic® F-127) is apolyoxyethylene-polyoxypropylene triblock copolymer in a ratio ofbetween about E₁₀₁ P₅₆ E₁₀₁ to about E₁₀₆ P₇₀ E₁₀₆, or about E₁₀₁P₅₆E₁₀₁, or about E₁₀₆ P₇₀ E₁₀₆, with an average molecular mass of about10,000 to about 15,000 Da, or about 12,000 to about 14,000 Da, or about12,000 to about 13,000 Da, or about 12,600 Da. For example, the NF formsof poloxamers or Pluronic® polymers can be used.

In some embodiments, the polymer can be, for example Pluronic® P103 orPluronic® P105. Pluronic® P103 is a block copolymer with an averagemolecular mass of about 3,000 Da to about 6,000 Da, or about 4,000 Da toabout 6,000 Da, or about 4,950 Da. Pluronic® P105 is a block copolymerwith an average molecular mass of about 5,000 Da to about 8,000 Da, orabout 6,000 Da to about 7,000 Da, or about 6,500 Da.

In some embodiments, the polymer can have an average molecular weight ofabout 9,000 Da or greater, about 10,000 Da or greater, about 11,000 Daor greater or about 12,000 Da or greater. In exemplary embodiments, thepolymer can have an average molecular weight of from about 10,000 toabout 15,000 Da, or about 12,000 to about 14,000 Da, or about 12,000 toabout 13,000 Da, or about 12,600 Da. In some embodiments, the polymercan be selected from Pluronic® P103, P105, F-68, F-87, F-108 and F-127,from Pluronic® P103, P105, F-87, F-108 and F-127, or from Pluronic®P103, P105, F-108 and F-127, or from Pluronic® P103, P105 and F-127. Insome embodiments, the polymer can be Pluronic® F-127. In representativeembodiments, the polymer is associated with the particles. For example,the polymer can be covalently attached to the particles. Inrepresentative embodiments, the polymer comprises polyethylene glycol,which is covalently attached to a selected polymer, yielding what iscommonly referred to as a PEGylated particle.

In some embodiments, a coating is non-covalently associated with a coreparticle. This association can be held together by any force ormechanism of molecular interaction that permits two substances to remainin substantially the same positions relative to each other, includingintermolecular forces, dipole-dipole interactions, van der Waals forces,hydrophobic interactions, electrostatic interactions and the like. Insome embodiments, the coating is adsorbed onto the particle. Accordingto representative embodiments, a non-covalently bound coating can becomprised of portions or segments that promote association with theparticle, for example by electrostatic or van der Waals forces. In someembodiments, the interaction is between a hydrophobic portion of thecoating and the particle. Embodiments include particle coatingcombinations which, however attached to the particle, present ahydrophilic region, e.g. a PEG rich region, to the environment aroundthe particle coating combination. The particle coating combination canprovide both a hydrophilic surface and an uncharged or substantiallyneutrally-charged surface, which can be biologically inert.

Suitable polymers for use according to the compositions and methodsdisclosed herein can be made up of molecules having hydrophobic regionsas well as hydrophilic regions. Without wishing to be bound by anyparticular theory, when used as a coating, it is believed that thehydrophobic regions of the molecules are able to form adsorptiveinteractions with the surface of the particle, and thus maintain anon-covalent association with it, while the hydrophilic regions orienttoward the surrounding, frequently aqueous, environment. In someembodiments the hydrophilic regions are characterized in that they avoidor minimize adhesive interactions with substances in the surroundingenvironment. Suitable hydrophobic regions in a coatings can include, forexample, PPO, vitamin E and the like, either alone or in combinationwith each other or with other substances. Suitable hydrophilic regionsin the coatings can include, for example, PEG, heparin, polymers thatform hydrogels and the like, alone or in combination with each other orwith other substances.

Representative coatings according to the compositions and methodsdisclosed herein can include molecules having, for example, hydrophobicsegments such as PPO segments with molecular weights of at least about1.8 kDa, or at least about 2 kDa, or at least about 2.4 kDa, or at leastabout 2.8 kDa, or at least about 3.2 kDa, or at least about 3.6 kDa, orat least about 4.0 kDa, or at least about 4.4 kDa, or at least about 4.8kDa or at least about 5.2 kDa, or at least 5.6 kDa, or at least 6.0 kDa,or at least 6.4 kDa or more. In some embodiments, the coatings can havePPO segments with molecular weights of from about 1.8 kDa to about 10kDa, or from about 2 kDa to about 5 kDa, or from about 2.5 kDa to about4.5 kDa, or from about 2.5 kDa to about 3.5 kDa. In some embodiments, atleast about 10%, or at least about 25%, or at least about 50%, or atleast about 75%, or at least about 90%, or at least about 95%, or atleast about 99% or more of the hydrophobic regions in these coatingshave molecular weights within these ranges. In some embodiments, thecoatings are biologically inert. Compounds that generate both ahydrophilic surface and an uncharged or substantially neutrally-chargedsurface can be biologically inert.

Representative coatings according to the compositions and methodsdisclosed herein can include molecules having, for example, hydrophobicsegments such as PEG segments with molecular weights of at least about1.8 kDa, or at least about 2 kDa, or at least about 2.4 kDa, or at leastabout 2.8 kDa, or at least about 3.2 kDa, or at least about 3.6 kDa, orat least about 4.0 kDa, or at least about 4.4 kDa, or at least about 4.8kDa, or at least about 5.2 kDa, or at least 5.6 kDa, or at least 6.0kDa, or at least 6.4 kDa or more. In some embodiments, the coatings canhave PEG segments with molecular weights of from about 1.8 kDa to about10 kDa, or from about 2 kDa to about 5 kDa, or from about 2.5 kDa toabout 4.5 kDa, or from about 2.5 kDa to about 3.5 kDa. In someembodiments, at least about 10%, or at least about 25%, or at leastabout 50%, or at least about 75%, or at least about 90%, or at leastabout 95%, or at least about 99% or more of the hydrophobic regions inthese coatings have molecular weights within these ranges. In someembodiments, the coatings are biologically inert. Compounds thatgenerate both a hydrophilic surface and an uncharged or substantiallyneutrally-charged surface can be biologically inert.

Representative coatings according to the compositions and methodsdisclosed herein can include molecules having, for example, segmentssuch as PLGA segments with molecular weights of at least about 4 kDa, orat least about 8 kDa, or at least about 12 kDa, or at least about 16kDa, or at least about 20 kDa, or at least about 24 kDa, or at leastabout 28 kDa, or at least about 32 kDa, or at least about 36 kDa, or atleast about 40 kDa, or at least about 44 kDa, of at least about 48 kDa,or at least about 52 kDa, or at least about 56 kDa, or at least about 60kDa, or at least about 64 kDa, or at least about 68 kDa, or at leastabout 72 kDa, or at least about 76 kDa, or at least about 80 kDa, or atleast about 84 kDa, or at least about 88 kDa or more. In someembodiments, at least about 10%, or at least about 25%, or at leastabout 50%, or at least about 75%, or at least about 90%, or at leastabout 95%, or at least about 99% or more of the regions in thesecoatings have molecular weights within these ranges. In someembodiments, the coatings are biologically inert. Compounds thatgenerate both a hydrophilic surface and an uncharged or substantiallyneutrally-charged surface can be biologically inert.

In some embodiments, s coating can include, for example, one or more ofthe following: anionic proteins (e.g., bovine serum albumin),surfactants (e.g., cationic surfactants such as for exampledimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives(e.g., cyclodextrin), nucleic acids, polymers (e.g., heparin), mucolyticagents, N-acetylcysteine, mugwort, bromelain, papain, clerodendrum,acetylcysteine, bromhexine, carbocisteine, eprazinone, mesna, ambroxol,sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosinβ4, dornase alfa, neltenexine, erdosteine, various DNases includingrhDNase, agar, agarose, alginic acid, amylopectin, amylose, beta-glucan,callose, carrageenan, cellodextrins, cellulin, cellulose, chitin,chitosan, chrysolaminarin, curdlan, cyclodextrin, dextrin, ficoll,fructan, fucoidan, galactomannan, gellan gum, glucan, glucomannan,glycocalyx, glycogen, hemicellulose, hydroxyethyl starch, kefiran,laminarin, mucilage, glycosaminoglycan, natural gum, paramylon, pectin,polysaccharide peptide, schizophyllan, sialyl lewis x, starch, starchgelatinization, sugammadex, xanthan gum, xyloglucan,L-phosphatidylcholine (PC), 1,2-dipalmitoylphosphatidycholine (DPPC),oleic acid, sorbitan trioleate, sorbitan monooleate, sorbitanmonolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene(20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2)ether, stearyl polyoxyethylene (2) ether, polyoxyethylene (4) laurylether, block copolymers of oxyethylene and oxypropylene, syntheticlecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyloleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate,glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethyleneglycol 400, cetyl pyridinium chloride, benzalkonium chloride, olive oil,glyceryl monolaurate, corn oil, cotton seed oil, sunflower seed oil,lecithin, oleic acid, sorbitan trioleate, and combinations of two ormore of any of the foregoing.

A particle-coating combinations can be made up of any combination ofparticle and coating substances disclosed or suggested herein. Examplesof such combinations include, for example, polystyrene-PEG, orPLGA-Pluronic® F-127.

In one aspect of the present invention, an effective amount of an activecompound as described herein is incorporated into a nanoparticle, e.g.for convenience of delivery and/or extended release delivery. The use ofmaterials in nanoscale provides one the ability to modify fundamentalphysical properties such as solubility, diffusivity, blood circulationhalf-life, drug release characteristics, and/or immunogenicity. Thesenanoscale agents may provide more effective and/or more convenientroutes of administration, lower therapeutic toxicity, extend the productlife cycle, and ultimately reduce health-care costs. As therapeuticdelivery systems, nanoparticles can allow targeted delivery andcontrolled release.

In another aspect of the present invention, the nanoparticle ormicroparticle is coated with a surface agent that facilitates passage ofthe particle through mucus. Said nanoparticles and microparticles have ahigher concentration of surface agent than has been previously achieved,leading to the unexpected property of extremely fast diffusion throughmucus. The present invention further comprises a method of producingsaid particles. The present invention further comprises methods of usingsaid particles to treat a patient.

A number of companies have developed microparticles for treatment of eyedisorders that can be used in conjunction with the present invention.For example, Allergan has disclosed a biodegradable microsphere todeliver a therapeutic agent that is formulated in a high viscositycarrier suitable for intraocular injection or to treat a non-oculardisorder (see U.S. publication 2010/0074957 and U.S. publication2015/0147406). In one embodiment, the '957 application describes abiocompatible, intraocular drug delivery system that includes aplurality of biodegradable microspheres, a therapeutic agent, and aviscous carrier, wherein the carrier has a viscosity of at least about10 cps at a shear rate of 0.1/second at 25° C. Allergan has alsodisclosed a composite drug delivery material that can be injected intothe eye of a patient that includes a plurality of microparticlesdispersed in a media, wherein the microparticles contain a drug and abiodegradable or bioerodible coating and the media includes the drugdispersed in a depot-forming material, wherein the media composition maygel or solidify on injection into the eye (see WO 2013/112434 A1,claiming priority to Jan. 23, 2012). Allergan states that this inventioncan be used to provide a depot means to implant a solid sustained drugdelivery system into the eye without an incision. In general, the depoton injection transforms to a material that has a viscosity that may bedifficult or impossible to administer by injection. In addition,Allergan has disclosed biodegradable microspheres between 40 and 200 μmin diameter, with a mean diameter between 60 and 150 μm that areeffectively retained in the anterior chamber of the eye withoutproducing hyperemia, see, US 2014/0294986. The microspheres contain adrug effective for an ocular condition with greater than seven dayrelease following administration to the anterior chamber of the eye. Theadministration of these large particles is intended to overcome thedisadvantages of injecting 1-30 μm particles which are generally poorlytolerated.

In another embodiment any of the above delivery systems can be used tofacilitate or enhance delivery through mucus.

Common techniques for preparing particles include, but are not limitedto, solvent evaporation, solvent removal, spray drying, phase inversion,coacervation, and low temperature casting. Suitable methods of particleformulation are briefly described below. Pharmaceutically acceptableexcipients, including pH modifying agents, disintegrants, preservatives,and antioxidants, can optionally be incorporated into the particlesduring particle formation.

Solvent Evaporation

In this method, the drug (or polymer matrix and one or more Drugs) isdissolved in a volatile organic solvent, such as methylene chloride. Theorganic solution containing the drug is then suspended in an aqueoussolution that contains a surface active agent such as poly(vinylalcohol). The resulting emulsion is stirred until most of the organicsolvent evaporated, leaving solid nanoparticles. The resultingnanoparticles are washed with water and dried overnight in alyophilizer. Nanoparticles with different sizes and morphologies can beobtained by this method.

Drugs which contain labile polymers, such as certain polyanhydrides, maydegrade during the fabrication process due to the presence of water. Forthese polymers, the following two methods, which are performed incompletely anhydrous organic solvents, can be used.

Solvent Removal

Solvent removal can also be used to prepare particles from drugs thatare hydrolytically unstable. In this method, the drug (or polymer matrixand one or more Drugs) is dispersed or dissolved in a volatile organicsolvent such as methylene chloride. This mixture is then suspended bystirring in an organic oil (such as silicon oil) to form an emulsion.Solid particles form from the emulsion, which can subsequently beisolated from the supernatant. The external morphology of spheresproduced with this technique is highly dependent on the identity of thedrug.

In one embodiment a compound of the present invention is administered toa patient in need thereof as particles formed by solvent removal. Inanother embodiment the present invention provides particles formed bysolvent removal comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by solvent removal comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by solvent removal comprisea compound of the present invention, an additional therapeutic agent,and one or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by solvent removal canbe formulated into a tablet and then coated to form a coated tablet. Inan alternative embodiment the particles formed by solvent removal areformulated into a tablet but the tablet is uncoated.

Spray Drying

In this method, the drug (or polymer matrix and one or more Drugs) isdissolved in an organic solvent such as methylene chloride. The solutionis pumped through a micronizing nozzle driven by a flow of compressedgas, and the resulting aerosol is suspended in a heated cyclone of air,allowing the solvent to evaporate from the micro droplets, formingparticles. Particles ranging between 0.1-10 microns can be obtainedusing this method.

In one embodiment a compound of the present invention is administered toa patient in need thereof as a spray dried dispersion (SDD). In anotherembodiment the present invention provides a spray dried dispersion (SDD)comprising a compound of the present invention and one or morepharmaceutically acceptable excipients as defined herein. In anotherembodiment the SDD comprises a compound of the present invention and anadditional therapeutic agent. In a further embodiment the SDD comprisesa compound of the present invention, an additional therapeutic agent,and one or more pharmaceutically acceptable excipients. In anotherembodiment any of the described spray dried dispersions can be coated toform a coated tablet. In an alternative embodiment the spray drieddispersion is formulated into a tablet but is uncoated.

Phase Inversion

Particles can be formed from drugs using a phase inversion method. Inthis method, the drug (or polymer matrix and one or more Drugs) isdissolved in a “good” solvent, and the solution is poured into a strongnon solvent for the drug to spontaneously produce, under favorableconditions, microparticles or nanoparticles. The method can be used toproduce nanoparticles in a wide range of sizes, including, for example,about 100 nanometers to about 10 microns, typically possessing a narrowparticle size distribution.

In one embodiment a compound of the present invention is administered toa patient in need thereof as particles formed by phase inversion. Inanother embodiment the present invention provides particles formed byphase inversion comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by phase inversion comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by phase inversion comprisea compound of the present invention, an additional therapeutic agent,and one or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by phase inversion canbe formulated into a tablet and then coated to form a coated tablet. Inan alternative embodiment the particles formed by phase inversion areformulated into a tablet but the tablet is uncoated.

Coacervation

Techniques for particle formation using coacervation are known in theart, for example, in GB-B-929 406; GB-B-929 40 1; and U.S. Pat. Nos.3,266,987, 4,794,000, and 4,460,563. Coacervation involves theseparation of a drug (or polymer matrix and one or more Drugs) solutioninto two immiscible liquid phases. One phase is a dense coacervatephase, which contains a high concentration of the drug, while the secondphase contains a low concentration of the drug. Within the densecoacervate phase, the drug forms nanoscale or microscale droplets, whichharden into particles. Coacervation may be induced by a temperaturechange, addition of a non-solvent or addition of a micro-salt (simplecoacervation), or by the addition of another polymer thereby forming aninterpolymer complex (complex coacervation).

In one embodiment a compound of the present invention is administered toa patient in need thereof as particles formed by coacervation. Inanother embodiment the present invention provides particles formed bycoacervation comprising a compound of the present invention and one ormore pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by coacervation comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by coacervation comprise acompound of the present invention, an additional therapeutic agent, andone or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by coacervation can beformulated into a tablet and then coated to form a coated tablet. In analternative embodiment the particles formed by coacervation areformulated into a tablet but the tablet is uncoated.

Low Temperature Casting

Methods for very low temperature casting of controlled releasemicrospheres are described in U.S. Pat. No. 5,019,400 to Gombotz et al.In this method, the drug (or polymer matrix and Sunitinib) is dissolvedin a solvent. The mixture is then atomized into a vessel containing aliquid non-solvent at a temperature below the freezing point of the drugsolution which freezes the drug droplets. As the droplets andnon-solvent for the drug are warmed, the solvent in the droplets thawsand is extracted into the non-solvent, hardening the microspheres.

In one embodiment a compound of the present invention is administered toa patient in need thereof as particles formed by low temperaturecasting. In another embodiment the present invention provides particlesformed by low temperature casting comprising a compound of the presentinvention and one or more pharmaceutically acceptable excipients asdefined herein. In another embodiment the particles formed by lowtemperature casting comprise a compound of the present invention and anadditional therapeutic agent. In a further embodiment the particlesformed by low temperature casting comprise a compound of the presentinvention, an additional therapeutic agent, and one or morepharmaceutically acceptable excipients. In another embodiment any of thedescribed particles formed by low temperature casting can be formulatedinto a tablet and then coated to form a coated tablet. In an alternativeembodiment the particles formed by low temperature casting areformulated into a tablet but the tablet is uncoated.

V. Controlled Release of Therapeutic Agent

The rate of release of the therapeutic agent can be related to theconcentration of therapeutic agent dissolved in polymeric material. Inmany embodiments, the polymeric composition includes non-therapeuticagents that are selected to provide a desired solubility of thetherapeutic agent. The selection of polymer can be made to provide thedesired solubility of the therapeutic agent in the matrix, for example,a hydrogel may promote solubility of hydrophilic material. In someembodiments, functional groups can be added to the polymer to increasethe desired solubility of the therapeutic agent in the matrix. In someembodiments, additives may be used to control the release kinetics oftherapeutic agent, for example, the additives may be used to control theconcentration of therapeutic agent by increasing or decreasingsolubility of the therapeutic agent in the polymer so as to control therelease kinetics of the therapeutic agent. The solubility may becontrolled by including appropriate molecules and/or substances thatincrease and/or decrease the solubility of the dissolved from of thetherapeutic agent to the matrix. The solubility of the therapeutic agentmay be related to the hydrophobic and/or hydrophilic properties of thematrix and therapeutic agent. Oils and hydrophobic molecules and can beadded to the polymer to increase the solubility of hydrophobic treatmentagent in the matrix.

Instead of or in addition to controlling the rate of migration based onthe concentration of therapeutic agent dissolved in the matrix, thesurface area of the polymeric composition can be controlled to attainthe desired rate of drug migration out of the composition. For example,a larger exposed surface area will increase the rate of migration of theactive agent to the surface, and a smaller exposed surface area willdecrease the rate of migration of the active agent to the surface. Theexposed surface area can be increased in any number of ways, forexample, by any of castellation of the exposed surface, a porous surfacehaving exposed channels connected with the tear or tear film,indentation of the exposed surface, protrusion of the exposed surface.The exposed surface can be made porous by the addition of salts thatdissolve and leave a porous cavity once the salt dissolves. In thepresent invention, these trends can be used to decrease the release rateof the active material from the polymeric composition by avoiding thesepaths to quicker release. For example, the surface area can beminimized, or channels avoided.

Further, an implant may be used that includes the ability to release twoor more drugs in combination, for example, the structure disclosed inU.S. Pat. No. 4,281,654 (Shell), for example, in the case of glaucomatreatment, it may be desirable to treat a patient with multipleprostaglandins or a prostaglandin and a cholinergic agent or anadrenergic antagonist (beta blocker), for example, Alphagan (Allegan,Irvine, Calif., USA), or a prostaglandin and a carbonic anhydraseinhibitor.

In addition, drug impregnated meshes may be used, for example, thosedisclosed in U.S. Patent Application Publication No. 2002/0055701 orlayering of biostable polymers as described in U.S. Patent ApplicationPublication No. 2005/0129731. Certain polymer processes may be used toincorporate drug into the devices, as described herein, for example,so-called “self-delivering drugs” or Polymer Drugs (PolymerixCorporation, Piscataway, N.J., USA) are designed to degrade only intotherapeutically useful compounds and physiologically inert linkermolecules, further detailed in U.S. Patent Application Publication No.2005/0048121 (East), hereby incorporated by reference in its entirety.Such delivery polymers may be employed in the devices, as describedherein, to provide a release rate that is equal to the rate of polymererosion and degradation and is constant throughout the course oftherapy. Such delivery polymers may be used as device coatings or in theform of microspheres for a drug depot injectable (for example, areservoir described herein). A further polymer delivery technology mayalso be adapted to the devices, as described herein, for example, thatdescribed in U.S. Patent Application Publication No. 2004/0170685(Carpenter), and technologies available from Medivas (San Diego, Calif.,USA).

VI. Process of Preparation of Compounds of Formula I, Formula II,Formula II′, Formula III, Formula IV, Formula V, Formula VI, FormulaIII′, Formula IV′, Formula V′, Formula VI′, Formula VII, Formula VII′,Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, FormulaXIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,Formula XX, Formula XXI, Formula XXII, or Formula XXIII Abbreviations

-   CAN Acetonitrile-   Ac Acetyl-   Ac₂O Acetic anhydride-   AcOEt, EtOAc ethyl acetate-   AcOH Acetic acid-   Boc₂O di-tert-butyl dicarbonate-   Bu Butyl-   CAN Ceric ammonium nitrate-   CBz Carboxybenzyl-   CDI Carbonyldiimidazole-   CH₃OH, MeOH Methanol-   CsF Cesium fluoride-   CuI Cuprous iodide-   DCM, CH₂Cl₂ Dichloromethane-   DIEA, DIPEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DMAP 4-Dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMS Dimethyl sulfide-   DMSO Dimethylsulfoxide-   DPPA Diphenyl phosphoryl azide-   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et Ethyl-   Et₃N, TEA Triethylamine-   EtOAc Ethylacetate-   EtOH Ethanol-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide    hexafluorophosphate-   HCl Hydrochloric acid-   HOBT Hydroxybenzotriazole-   iBu, i-Bu, isoBu Isobutyl-   iPr, i-Pr, isoPr Isopropyl-   iPr₂NEt N,N-diisopropylethylamine-   K₂CO₃ Potassium carbonate-   K₂CO₃ Potassium carbonate-   LiOH Lithium hydroxide-   Me Methyl-   MeI Methyl iodide-   Ms Mesyl-   MsCl Mesylchloride-   MTBE Methyl tbutylether-   Na₂SO₄ Sodium sulfate-   NaCl Sodium chloride-   NaH Sodium hydride-   NaHCO₃ Sodium bicarbonate-   NBS N-bromo succinimide-   NCS N-chloro succinimide-   NEt₃ Trimethylamine-   NMP N-Methyl-2-pyrrolidone-   PCC Pyridinium chlorochromate-   Pd (OAc)₂ Palladium acetate-   Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)    ferrocene]dichloropalladium(II)-   Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloride-   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)-   Pd/C Palladium on carbon-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   PMB 4-Methoxybenzyl ether-   PPh₃ Triphenylphosphine-   Pr Propyl-   Py, py Pyridine-   RT Room temperature-   TBAF Tetra-n-butylammonium fluoride-   TBAT Tetrabutylammonium difluorotriphenylsilicate-   tBu, t-Bu Tertbutyl-   tBuOK Potassium tert-butoxide-   TEA Trimethylamine-   Tf₂O Trifluoromethanesulfonic anhydride-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TMS Trimethylsilane-   TMSBr Bromotrimethylsilane-   t_(R) Retention time-   Troc 2,2,2-Trichlorethoxycarbonyl chloride-   Zn (CN)₂ Zinc cyanide

General Methods

All nonaqueous reactions were performed under an atmosphere of dry argonor nitrogen gas using anhydrous solvents. The progress of reactions andthe purity of target compounds were determined using one of the twoliquid chromatography (LC) methods listed below. The structure ofstarting materials, intermediates, and final products was confirmed bystandard analytical techniques, including NMR spectroscopy and massspectrometry.

Example 1. Synthetic Examples of Ester Intermediates for the Preparationof Final Prodrugs

Step 1: (S)-2-Hydroxy-propionic acid (S)-1-benzyloxycarbonyl-ethyl ester(1-2)

To a solution of (3S,6S)-3,6-dimethyl-[1,4]dioxane-2,5-dione (1-1) (5.0g, 34.72 mmol) in toluene (100 mL) was added benzyl alcohol (3.2 mL,31.72 mmol) and camphorsulfonic acid (0.8 g, 3.47 mmol) at 25-30° C.After stirring at 80° C. for 2 hours, the resulting reaction mixture wasdiluted with ethyl acetate (800 mL) and washed with water (2×400 mL).Following evaporation of volatiles, the reaction mixture was purified bysilica gel (230-400) column chromatography (5% methanol indichloromethane) to afford product 1-2 as a pale yellow liquid (8.0 g,91%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.41-7.32 (m, 5H), 5.48 (d, J=5.6 Hz,1H), 5.15 (s, 2H), 5.1 (q, J=8.0 Hz, 1H), 4.20-4.18 (m, 1H), 1.42 (d,J=7.2 Hz, 3H), 1.16 (d, J=7.2 Hz, 3H). MS m/z (M+H) 253.4; MS m/z(M+NH₄) 270.3.

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-3)

To a solution of (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (0.1 g, 0.23 mmol) indichloromethane (2 mL) was added triethylamine (0.23 mL, 1.61 mmol),TBDPS-Cl (0.43 mL, 1.618 mmol), and a catalytic amount of4-dimethylaminopyridine at 0° C. After stirring at room temperature for8 hours, the resulting reaction mixture was quenched with water (20 mL)and extracted with ethyl acetate (2×50 mL). Evaporation of volatilesunder reduced pressure afforded product 1-3 as a colorless liquid (200mg, 74%).

Step 3: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-carboxy-ethyl ester (1-4)

A solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-3) (1.5 g) in methanol (20 mL)and 10% Pd/C (0.3 g, 50% wet) were added to a 100 mL autoclave vessel at25-30° C. The reaction mixture was stirred at room temperature underhydrogen pressure (5 kg/cm²) for 2 hours. After completion of thereaction, the reaction mixture was filtered through celite andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (60-120) columnchromatography (10% methanol in dichloromethane) to afford pure product1-4 as a colorless liquid (700 mg, 58%). ¹H NMR (400 MHz, DMSO-d₆) δ13.1 (bs, 1H), 7.63-7.62 (m, 4H), 7.62-7.37 (m, 6H), 4.77 (q, J=7.6 Hz,1H), 4.26 (q, J=8.0.0 Hz, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.23 (d, J=7.2Hz, 3H), 1.02 (s, 9H); MS m/z (M−H) 399.1.

Step 1: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester (2-2)

To a solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-carboxy-ethyl ester (1-4) (5.17 g, 7.22 mmol) in dichloromethane(10 mL) was added EDCI.HCl (2.12 g, 11.11 mmol), (S)-2-hydroxy-propionicacid benzyl ester (2-1) (1 g, 5.55 mmol), and 4-dimethylaminopyridine(670 mg, 0.55 mmol) at 0° C. The reaction mixture was allowed to stir at25° C. for 1 hour, and the resulting reaction mixture was diluted withethyl acetate (300 mL) and washed with water (2×50 mL). The crudeproduct obtained upon evaporation of volatiles was purified by silicagel (230-400) column chromatography (3% ethyl acetate in hexane) toafford product 2-2 as a colorless liquid (4.3 g, 88%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.62-7.61 (m, 4H), 7.60-7.33 (m, 11H), 5.19-5.14 (m, 3H),4.94 (q, J=6.8 Hz, 1H), 4.28 (q, J=6.8 Hz, 1H), 1.42 (d, J=7.2 Hz, 3H),1.31 (d, J=6.4 Hz, 3H), 1.23 (d, J=7.2 Hz, 3H), 1.02 (s, 9H); MS m/z(M+NH₄+) 580.3.

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester (2-3)

A solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester (2-2) (7.0 g,12.45) in methanol (40 mL) and 10% Pd/C (1.4 g, 50% wet) were added to a100 mL autoclave vessel at 25-30° C. The reaction mixture was stirred atroom temperature under hydrogen pressure (5 kg/cm²) for 2 hours. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(60-120) column chromatography (10% methanol in dichloromethane) toafford product 2-3 as a pale yellow liquid (5.8 g, 94%). ¹H NMR (400MHz, DMSO-d₆) δ 13.2 (bs, 1H), 7.61 (d, J=1.2 Hz, 4H), 7.60-7.40 (m,6H), 4.99-4.91 (m, 2H), 1.39 (d, J=7.2 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H),1.29 (d, J=6.8 Hz, 3H), 1.02 (s, 9H); MS m/z (M−H) 471.3.

Step 1: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (3-1)

To a solution of (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (6.0 g, 33.2 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-carboxy-ethyl ester (1-4) (17.3 g, 7.77 mmol) in dichloromethane(60 mL) was added EDCI.HCl (8.2 g, 43.2 mmol, 1.5 eq) and4-dimethylaminopyridine (405 mg, 3.3 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 1 hour, and the resulting reactionmixture was quenched with water (200 mL), extracted with dichloromethane(250×3 mL), dried over Na₂SO₄, and concentrated under reduced pressure.The crude product obtained upon evaporation of volatiles was purified bysilica gel (60-120) column chromatography (10% methanol indichloromethane) to afford product 3-1 as a pale yellow liquid (5.8 g,94%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (d, J=8 Hz, 4H), 7.49-7.33 (m,11H), 5.20-5.15 (m, 4H), 4.95 (q, J=7.2 Hz, 1H), 4.29 (q, J=6.4 Hz, 1H),1.43 (d, J=7.2 Hz, 3H), 1.39 (d, J=7.2 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H),1.28 (d, J=1.28 Hz, 3H), 1.02 (s, 9H); MS m/z (M+NH₄ ⁺) 652.8.

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethyl ester(3-2)

A solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (3-1) (700 mg, 1.10 mmol) in methanol (10 mL) and 10% Pd/C (140mg, 50% wet) were added to a 100 mL autoclave vessel at 25-30° C. Thereaction mixture was stirred at room temperature under hydrogen pressure(5 kg/cm²) for 2 hours. After completion of the reaction, the reactionmixture was filtered through celite and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (60-120) column chromatography (10% methanol indichloromethane) to afford product 3-2 as a pale yellow liquid (420 mg,78%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.2 (bs, 1H), 7.61-7.60 (m, 4H),7.59-7.40 (m, 6H), 5.16 (q, J=7.2 Hz 1H), 4.98-4.93 (m, 2H), 4.29 (q,J=6.8, 1H), 1.44 (d, J=7.2 Hz, 3H), 1.40 (d, J=7.2 Hz, 3H), 1.31-1.30(m, 6H), 1.01 (s, 9H); MS m/z (M+NH₄ ⁺) 562.3; MS m/z (M−H) 543.1.

Step 1: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (4-1)

EDCI.HCl (5.68 g, 29.76 mmol) and 4-dimethylaminopyridine (242 mg, 1.98mmol) were added to a solution of (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (5.0 g, 19.84 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester (2-3) (12.1 g, 25.79mmol) in dichloromethane (50 mL) at 0° C. The reaction mixture wasallowed to stir at 25-30° C. for 1 hour, and the resulting reactionmixture was quenched with water (200 mL), extracted with dichloromethane(250×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (230-400) column chromatography (6% ethyl acetatein hexane) to afford product 4-1 as a pale yellow liquid (9.1 g, 65%).

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (4-2)

A solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (4-1) (9.1 g, 12.88 mmol) in methanol (50 mL) and 10% Pd/C (1.9 g,50% wet) were added to a 100 mL autoclave vessel at 25-30° C. Thereaction mixture was stirred at room temperature under hydrogen pressure(5 kg/cm²) over a period of 2 hours. After completion of the reaction,the reaction mixture was filtered through celite and concentrated underreduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (60-120) column chromatography (10%methanol in dichloromethane) to afford product 4-2 as a pale yellowliquid (6.2 g, 78%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.1 (bs, 1H),7.61-7.59 (m, 4H), 7.49-7.40 (m, 6H), 5.20-5.14 (m, 2H), 5.0-4.92 (m,2H), 4.30-4.26 (m, 1H), 1.47-1.41 (m, 9H), 1.40-1.30 (m, 6H), 1.01 (s,9H); MS m/z (M−H) 615.4.

Step 1: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (5-1)

To a solution of (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (6.0 g, 23.8 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethyl ester(3-2) (16.8 g, 30.95 mmol) in dichloromethane (60 mL) was added EDCI.HCl(6.81 g, 35.7 mmol) and 4-dimethylaminopyridine (290 mg, 2.38 mmol) at0° C. The reaction mixture was allowed to stir at 25-30° C. over aperiod of 1 hour, and the resulting reaction mixture was quenched withwater (200 mL), extracted with dichloromethane (250×3 mL), dried oversodium sulfate, and concentrated under reduced pressure. The crudeproduct obtained upon evaporation of volatiles was purified by silicagel (230-400) column chromatography (6% ethyl acetate in hexane) toafford product 5-1 as a pale yellow liquid (8.3 g, 46%). ¹H NMR (400MHz, DMSO-d₆) δ 7.64-7.56 (m, 4H), 7.53-7.29 (m, 11H), 5.24-5.08 (m,6H), 4.95 (q, J=7.0 Hz, 1H), 4.29 (q, J=6.7 Hz, 1H), 1.50-1.20 (m, 12H),1.02 (m, 6H), 1.01 (s, 9H); MS m/z (M+H) 796.7.

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (5-2)

A solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (5-1) (8.3 g, 10.66 mmol) in methanol (40 mL) and 10% Pd/C (1.7 g,50% wet) were added to a 250 mL autoclave vessel at 25-30° C. Thereaction mixture was stirred at room temperature under hydrogen pressure(5 kg/cm²) for 2 hours. After completion of the reaction, the reactionmixture was filtered through celite and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (60-120) column chromatography (10% methanol indichloromethane) to afford product 5-2 as a pale yellow liquid (5.9 g,81%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (bs, 1H), 7.64-7.57 (m, 4H),7.54-7.37 (m, 6H), 5.15-5-21 (m, 3H), 5.01-4.92 (m, 2H), 4.29 (q, J=6.7Hz, 1H), 1.47-1.44 (m, 12H), 1.23-1.28 (m, 6H), 1.04 (s, 9H); MS m/z(M−H) 687.6.

Step 1: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (6-1)

EDCI.HCl (3.17 g 0.16.64 mmol) and 4-dimethylaminopyridine (135 mg, 1.10mmol) were added to a solution of (S)-2-hydroxy-propionic acid benzylester (2-1) (2 g, 11.09 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (5-2) (9.93 g, 14.42 mmol) in dichloromethane (20 mL) at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (7% ethyl acetate in hexane) to afford product 6-1 as apale yellow liquid (5.1 g, 53%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.64-7.56(m, 4H), 7.53-7.30 (m, 11H), 5.24-5.15 (m, 7H), 4.95 (q, J=8 Hz, 1H),4.29 (q, J=6.7 Hz, 1H), 1.48-1.41 (m, 15H), 1.35-1.21 (m, 6H), 1.02 (s,9H); MS m/z (M+NH₄ ⁺) 868.9.

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (6-2)

(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-oxycarbonylnyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (6-1) (5.1 g, 6.00 mmol) in methanol (30 mL) and 10% Pd/C (1.14 g,50% wet) were added to a 250 mL autoclave vessel at 25-30° C. Thereaction mixture was stirred at room temperature under hydrogen pressure(5 kg/cm²) for 2 hours. After completion of the reaction, the reactionmixture was filtered through celite and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (60-120) column chromatography (12% methanol indichloromethane) to afford product 6-2 as a pale yellow liquid (3.66 g,80%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.61 (bs, 1H), 7.62-7.60 (m, 4H),7.41-7.51 (m, 6H), 5.1-5.3 (m, 4H), 4.90-4.89 (m, 2H), 4.3 (q, J=6.8 Hz,1H), 1.50-1.37 (m, 15H), 1.35-1.18 (m, 6H), 1.02 (s, 9H); MS m/z (M+NH₄⁺) 778.9.

Step 1: (S)-2-Hydroxy-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (7-1)

To a solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (4-1) (3.8 g, 5.38 mmol) in tetrahydrofuran (40 mL) were addedtetra-n-butylammonium fluoride (8.09 mL, 1.0 M, 8.07 mmol) and aceticacid (0.48 g, 8.07 mmol) at 0° C. The reaction mixture was allowed tostir at room temperature over a period of 1 hour. The resulting reactionmixture was concentrated under reduced pressure and crude productobtained upon evaporation of the volatiles was purified by silica gelcolumn chromatography (20% ethyl acetate in hexane) to afford product7-1 as colorless liquid (1.3 g, 51%). ¹H NMR (400 MHz, DMSO-d₆) δ7.44-7.30 (m, 5H), 5.49 (d, J=5.9 Hz, 1H), 5.24-5.07 (m, 5H), 4.21 (m,1H), 1.51-1.36 (m, 12H), 1.20 (d, J=6.8 Hz, 3H); MS m/z (M+NH₄ ⁺) 486.3

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (7-2)

To a solution of (S)-2-hydroxy-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (7-1) (1.5 g, 3.20 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (4-2) (3.35 g, 5.44 mmol) in dichloromethane (50 mL) was addedEDCI.HCl (1.22 g, 6.4 mmol), hydroxybenzotriazole (88 mg, 0.64 mmol),and 4-dimethylaminopyridine (39 mg, 0.32 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. over a period of 1 hour and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (150×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (16% ethyl acetate in hexane) to afford product 7-2 as apale yellow liquid (1.4 g, 41%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (d,J=5.6 Hz, 4H), 7.53-7.30 (m, 11H), 5.25-5.11 (m, 9H), 4.95 (q, J=7.0 Hz,1H), 4.29 (q, J=6.7 Hz, 1H), 1.50-1.37 (m, 24H), 1.35-1.21 (m, 6H), 1.02(s, 9H); MS m/z (M+NH₄ ⁺) 1084.6.

Step 3: Compound 7-3 (PLA (n=10)-O-TBDPS)

A solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (7-2) (1.4 g, 1.31 mmol) in methanol (15 mL) and 10% Pd/C (0.28 g,50% wet) was added to a 100 mL autoclave vessel at 25-30° C. Thereaction mixture was stirred at room temperature under hydrogen pressure(5 kg/cm²) over a period of 2 hours. After completion of the reaction,the reaction mixture was filtered through celite and concentrated underreduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (60-120) column chromatography (10%methanol in dichloromethane) to afford product 7-3 as a pale yellowliquid (0.9 g, 70%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.64-7.57 (d, J=7.2 Hz,4H), 7.53-7.37 (m, 6H), 5.20-5.19 (m, 7H), 4.99-4.92 (m, 2H), 4.26-4.31(m, 1H), 1.50-1.37 (m, 24H), 1.28-1.30 (m, 6H), 1.02 (s, 9H); MS m/z(M+NH₄ ⁺) 994.5

Step 1: (S)-2-Hydroxy-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (8-1)

To a solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester 5-1 (6.0 g, 7.71 mmol) in tetrahydrofuran (60 mL) was addedtetra-n-butyl ammonium fluoride (11.5 mL, 1.0 M, 11.56 mmol) and aceticacid (0.69 g, 11.56 mmol) at 0° C. The reaction mixture was allowed tostir at room temperature for 1 hour, and the resulting reaction mixturewas concentrated under reduced pressure. The crude product obtained uponevaporation of the volatiles was purified by silica gel columnchromatography (22% ethyl acetate in hexane) to afford product 8-1 ascolorless liquid (1.7 g, 41%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.43-7.30 (m,5H), 5.49 (d, J=5.9 Hz, 1H), 5.25-5.07 (m, 7H), 4.26-4.15 (m, 1H),1.51-1.37 (m, 15H), 1.34-1.28 (m, 3H); MS m/z (M+NH₄ ⁺) 558.1.

Step 2:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-(Benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (8-2)

To solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester 5.2 (2.81 g, 4.09 mmol) and (S)-2-hydroxy-propionic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (8-1) (1.7 g, 3.14 mmol) in dichloromethane (20 mL) was addedEDCI.HCl (1.2 g, 6.296 mmol), hydroxybenzotriazole (86 mg, 0.62 mmol),and 4-dimethylaminopyridine (38 mg, 0.314 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. over a period of 1 hour. Theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (150×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (18% ethyl acetate in hexane) to afford product (8-2) asa pale yellow liquid 1.5 g (39%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (d,J=8.0 Hz, 4H), 7.59-7.32 (m, 11H), 5.25-5.13 (m, 12H), 4.95 (q, J=7.0Hz, 1H), 4.28 (d, J=6.4 Hz, 1H), 1.35-1.50 (m, 30H), 1.26-0.98 (m, 6H),0.90 (s, 9H); MS m/z (M+NH₄ ⁺) 1228.6.

Step 3: Compound 8-3 (PLA (n=12)-O-TBDPS)

A solution of(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-(benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (8-2) (1.5 g, 1.23 mmol)in methanol (15 mL) and 10% Pd/C (0.30 g, 50% wet) were added to a 100mL autoclave vessel at 25-30° C. The reaction mixture was stirred atroom temperature under hydrogen pressure (5 kg/cm²) over a period of 2hours. After completion of the reaction, the reaction mixture wasfiltered through celite and concentrated under reduced pressure. Thecrude product obtained upon evaporation of volatiles was purified bysilica gel (60-120) column chromatography (10% methanol indichloromethane) to afford product 8-3 as a pale yellow liquid 1.1 g(80%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.62 (d, J=7.2 Hz, 4H), 7.51-7.37 (m,6H), 5.76 (s, 4H), 5.25-5.12 (m, 8H), 1.50-1.36 (m, 26H), 1.28-1.30 (m,10H), 1.02 (s, 9H); MS m/z (M+NH₄₊) 1138.4.

Step 1: (S)-2-Hydroxy-propionic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (9-1)

To a solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((i)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (6-1) (6.0 g, 7.05 mmol) in tetrahydrofuran (60 mL) was addedtetra-n-butyl ammonium fluoride (10.5 mL, 1.0 M, 10.57 mmol) and aceticacid (0.63 g, 10.57 mmol) at 0° C. The reaction mixture was allowed tostir at room temperature over a period of 1 hour, and the resultingreaction mixture was concentrated under reduced pressure. The crudeproduct obtained upon evaporation of the volatiles was purified bysilica gel column chromatography (22% ethyl acetate in hexane) to affordproduct 9-1 as colorless liquid 2.5 g (58%). ¹H NMR (400 MHz, DMSO-d₆) δ7.44-7.30 (m, 5H), 5.49 (d, J=5.9 Hz, 1H), 5.25-5.12 (m, 7H), 5.16-5.07(m, 1H), 4.26-4.15 (m, 1H), 1.51-1.37 (m, 18H), 1.31-1.13 (m, 3H); MSm/z (M+NH₄ ⁺) 630.7

Step 2:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-(Benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (9-2)

To a solution of (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (6-2) (4.65 g, 6.127 mmol) and (S)-2-hydroxy-propionic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (9-1) (2.5 g, 4.08 mmol) in dichloromethane (25 mL) was addedEDCI.HCl (1.56 g, 8.168 mmol), hydroxybenzotriazole (112 mg, 0.816mmol), and 4-dimethylaminopyridine (49 mg, 0.816 mmol) at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour. Theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (150×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (18% ethyl acetate in hexane) to afford product 9-2 as apale yellow liquid 3.4 g (61%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (dt,J=7.8, 1.4 Hz, 4H), 7.53-7.34 (m, 11H), 5.25-5.11 (m, 14H), 4.94 (q,J=7.6 Hz, 1H), 4.28 (q, J=7.1 Hz, 1H), 1.49-1.37 (m, 36H), 1.35-1.21 (m,6H), 1.02 (s, 9H); MS m/z (M+NH₄) 1373.2

Step 3: Compound 9-3 (PLA (n=14)-O-TBDPS)

A solution of(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-(benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (9-2) (3.4 g, 2.50 mmol) in methanol (25 mL)and 10% Pd/C (0.70 g, 50% wet) were added to a 100 mL autoclave vesselwere added at 25-30° C. The reaction mixture was stirred at roomtemperature under hydrogen pressure (5 kg/cm²) over a period of 2 hours.After completion of the reaction, the reaction mixture was filteredthrough celite and concentrated under reduced pressure. The crudeproduct obtained upon evaporation of volatiles was purified by silicagel (60-120) column chromatography (10% methanol in dichloromethane) toafford product 9-3 as a pale yellow liquid 2.5 g (83%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.64-7.57 (m, 4H), 7.51-7.37 (m, 6H), 5.25-5.09 (m, 11H),4.93-4.95 (m, 2H), 4.28 (q, J=6.8, 1H), 1.50-1.42 (m, 34H), 1.46-1.35(m, 3H), 1.32-1.30 (m, 6H), 1.02 (s, 9H); MS m/z (M+NH₄ ⁺) 1282.9.

Step 1: (S)-2-Acetoxy-propionic acid benzyl ester (10-1)

To a solution of (S)-2-hydroxy-propionic acid benzyl ester (2-1) (10 g,55.49 mmol) in dichloromethane (100 mL) was added4-dimethylaminopyridine (0.676 g, 5.54 mmol) and acetic anhydride (7.8mL, 83.24 mmol) at 0° C. The reaction mixture stirred at 25-30° C. for 3hours, and the resulting reaction mixture was quenched with water (200mL), extracted with ethyl acetate (2×200 mL), and dried over sodiumsulfate. Evaporation of volatiles under reduced pressure affordedproduct 10-1 as a pale yellow liquid (9.0 g, 97%).

Step 2: (S)-2-Acetoxy-propionic acid (10-2)

A solution of (S)-2-acetoxy-propionic acid benzyl ester (10-1) (9.0 g,40.54 mmol) in methanol (50 mL) and 10% Pd/C (1.8 g, 50% wet) were addedto a 250 mL autoclave vessel at 25-30° C. The reaction mixture wasstirred at room temperature under hydrogen pressure (5 kg/cm²) for 2hours, and following consumption of starting materials, the reactionmixture was filtered through celite. Evaporation of the volatiles underreduced pressure afforded product (10-2) as a pale yellow liquid 4.35 g(81%).

Step 3:(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-3)

To a solution of (S)-2-acetoxy-propionic acid (10-2) (4.35 g, 32.73mmol) and (S)-2-hydroxy-propionic acid (S)-1-benzyloxycarbonyl-ethylester (1-2) (5.5 g, 21.82 mmol) in dichloromethane (50 mL) was addedEDCI.HCl (8.33 g, 43.64 mmol) and 4-dimethylaminopyridine (266 mg, 2.182mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for1 hour. The resulting reaction mixture was quenched with water (100 mL),extracted with dichloromethane (150×3 mL), dried over sodium sulfate,and concentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (8% ethyl acetate in hexane) to afford product 10-3 as apale yellow liquid 4.6 g (58%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.36(m, 5H), 5.20-5.16 (m, 4H), 5.15-5.20 (q, J=7.1 Hz, 1H), 2.07 (s, 3H),1.50-1.38 (m, 9H); MS m/z (M+NH₄ ⁺) 384.2.

Step 4:(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-4)

A solution of(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-3) (4.6 g, 12.56 mmol) in methanol (30 mL) and 10% Pd/C (0.95 g, 50%wet) were added to a 100 mL autoclave vessel at 25-30° C. The reactionmixture was stirred at room temperature under hydrogen pressure (5kg/cm²) for 2 hours, and following consumption of starting materials,the reaction mixture was filtered through celite. Evaporation ofvolatiles under reduced pressure afforded product (10-4) as a paleyellow liquid (2.5 g, 71%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H),5.17 (q, J=7.1 Hz, 1H), 5.02 (dq, J=24.5, 7.1 Hz, 2H), 2.07 (s, 3H),1.50-1.38 (m, 9H); MS m/z (M−H) 275.1.

Step 1: (S)-2-((S)-2-Acetoxy-propionyloxy)-propionic acid benzyl ester(11-1)

To a solution of (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (5 g, 19.84 mmol) indichloromethane (50 mL) was added 4-dimethylaminopyridine (0.24 g, 1.984mmol) and acetic anhydride (2.8 mL, 29.76 mmol) at 0° C. The reactionmixture was stirred at 25-30° C. for 3 hours. And the resulting reactionmixture was quenched with water (200 mL), extracted with ethyl acetate(2×200 mL), and dried over sodium sulfate. Evaporation of volatilesunder reduced pressure afforded product 11-1 as a pale yellow liquid(7.3 g, 73%).

Step 2: (S)-2-((S)-2-Acetoxy-propionyloxy)-propionic acid (11-2)

A solution of (S)-2-((S)-2-acetoxy-propionyloxy)-propionic acid benzylester (11-1) (7.3 g, 24.82) in methanol (40 mL) and 10% Pd/C (1.5 g, 50%wet) was added to a 250 mL autoclave vessel at 25-30° C. The reactionmixture was stirred at room temperature under hydrogen pressure (5kg/cm²) for 2 hours. After completion of the reaction, the reactionmixture was filtered through celite. Evaporation of volatiles underreduced pressure afforded product 11-2 as a pale yellow liquid (4.4 g,81%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 5.00 (dq, J=20.0, 7.1Hz, 2H), 2.07 (s, 3H), 1.42 (dd, J=7.1, 6.3 Hz, 6H); MS m/z (M−H) 203.1.

Step 3:(S)-2-{(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionicacid benzyl ester (11-3)

To a solution of (S)-2-((S)-2-acetoxy-propionyloxy)-propionic acid(11-2) (4.3 g, 20.8 3 mmol) and (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (3.5 g, 13.88 mmol) indichloromethane (50 mL) was added EDCI.HCl (5.3 g, 27.76 mmol) and4-dimethylaminopyridine (169 mg, 1.38 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. for 1 hour. The resultingreaction mass was quenched with water (100 mL), extracted withdichloromethane (200×3 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (230-400) column chromatography (8%ethyl acetate in hexane) to afford product 11-3 as a pale yellow liquid(2.2 g, 36%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.43-7.30 (m, 5H), 5.24-5.08(m, 5H), 5.03 (q, J=7.2 Hz, 1H), 2.07 (s, 3H), 1.44-1.40 (m, 12H); MSm/z (M+NH₄ ⁺) 456.3.

Step 4:(S)-2-{(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionicacid (11-4)

A solution of(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionicacid benzyl ester (11-3) (2.2 g, 5.08 mmol) in methanol (15 mL) and 10%Pd/C (0.45 g, 50% wet) were added to a 100 mL autoclave vessel at 25-30°C. The reaction mixture was stirred at room temperature under hydrogenpressure (5 kg/cm²) over a period of 2 hours. After completion of thereaction, the reaction mixture was filtered through celite. Evaporationof volatiles under reduced pressure afforded product 11-4 as a paleyellow liquid (1.1 g, 65%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H),5.18 (qd, J=7.0, 3.1 Hz, 2H), 5.01 (dq, J=30.1, 7.1 Hz, 2H), 2.07 (s,3H), 1.51-1.37 (m, 12H); MS m/z (M−H) 347.1.

Step 1:(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionicacid benzyl ester (12-1)

To a solution of(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-4) (8.2 g, 29.76 mmol) and (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (5.0 g, 19.84 mmol) indichloromethane (50 mL) was added EDCI.HCl (7.57 g, 39.68 mmol) and4-dimethylaminopyridine (242 mg, 1.98 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. for 1 hour. The resultingreaction mass was quenched with water (100 mL), extracted withdichloromethane (200×3 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (230-400) column chromatography (6%ethyl acetate in hexane) to afford product 12-1 as a pale yellow liquid(6.2 g, 63%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.44-7.30 (m, 5H), 5.25-5.09(m, 6H), 5.05 (q, J=7.0 Hz, 1H), 2.07 (s, 3H), 1.51-1.37 (m, 15H); MSm/z (M+NH₄ ⁺) 528.3.

Step 2:(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionicacid (12-2)

A solution of(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionicacid benzyl ester (12-1) (6.2 g, 12.15 mmol) in methanol (30 mL) and 10%Pd/C (1.25 g, 50% wet) were added to a 100 mL autoclave vessel at 25-30°C. The reaction mixture was stirred at room temperature under hydrogenpressure (5 kg/cm²) for 2 hours. After completion of the reaction, thereaction mixture was filtered through celite. Evaporation of volatilesunder reduced pressure afforded product 12-2 as a pale yellow liquid(4.4 g, 86%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 5.25-5.14 (m,3H), 5.02 (dq, J=25.2, 7.0 Hz, 2H), 2.07 (s, 3H), 1.50-1.38 (m, 15H); MSm/z (M+NH₄ ⁺) 438.2.

Step 1:(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionyloxy]-propionicacid benzyl ester (13-1)

To a solution of(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionicacid (11-4) (12.4 g, 35.71 mmol) and (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (6.0 g, 23.80 mmol) indichloromethane (60 mL) was added EDCI.HCl (9.09 g, 47.60 mmol) and4-dimethylaminopyridine (290 mg, 2.38 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. for 1 hour. The resultingreaction mixture was quenched with water (100 mL), extracted withdichloromethane (200×3 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (230-400) column chromatography (6%ethyl acetate in hexane) to afford product 13-1 as a pale yellow liquid(8.3 g, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.44-7.30 (m, 5H), 5.25-5.10(m, 7H), 5.05 (q, J=7.0 Hz, 1H), 2.06 (s, 3H), 1.52-1.39 (m, 18H); MSm/z (M+NH₄ ⁺) 600.2.

Step 2:(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-Acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionyloxy]-propionicacid (13-2)

A solution of(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionyloxy]-propionicacid benzyl ester (13-1) (8.3 g, 14.26 mmol) in methanol (50 mL) and 10%Pd/C (1.65 g, 50% wet) were added to a 250 mL autoclave vessel at 25-30°C. The reaction mixture was stirred at room temperature under hydrogenpressure (5 kg/cm²) for 2 hours. After completion of the reaction, thereaction mixture was filtered through celite. Evaporation of volatilesunder reduced pressure afforded product 13-2 as a pale yellow liquid(5.7 g, 81%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 5.26-5.14 (m,4H), 5.02 (dq, J=24.0, 7.1 Hz, 2H), 2.07 (s, 3H), 1.51-1.38 (m, 18H); MSm/z (M−H) 491.1.

Step 1: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid benzylester (14-1)

To a solution of (S)-2-hydroxy-propionic acid benzyl ester 2-1 (5 g,27.77 mmol) in dichloromethane (50 mL) was added triethylamine (7.8 mL,55.55 mmol), TBDPS-Cl (14.6 mL, 55.55 mmol), and a catalytic amount of4-dimethylaminopyridine at 0° C. The reaction mixture was stirred atroom temperature for 8 hours, and the resulting reaction mixture wasquenched with water (200 mL) and extracted with ethyl acetate (2×150mL). Evaporation of volatiles under reduced pressure afforded product14-1 as pale yellow liquid (8.2 g, 70%).

Step 2: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid (14-2)

A solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acidbenzyl ester 14-1 (8.2 g, 19.61 mmol) in methanol (50 mL) and 10% Pd/C(1.6 g, 50% wet) were added to a 250 mL autoclave vessel at 25-30° C.The reaction mixture was stirred at room temperature under hydrogenpressure (5 kg/cm²) for 2 hours. After completion of the reaction, thereaction mixture was filtered through celite. Evaporation of volatilesunder reduced pressure afforded product 14-2 as a pale yellow liquid(4.9 g, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 7.62 (tt,J=6.8, 1.7 Hz, 4H), 7.55-7.33 (m, 6H), 4.16 (q, J=6.7 Hz, 1H), 1.31-1.13(m, 3H), 1.02 (s, 9H); MS m/z (M−H) 327.1.

Step 1: (S)-2-tert-Butoxy-propionic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxy carbonyl)-ethyl ester (15-2)

To a solution of (S)-2-tert-butoxy-propionic acid (15-1) (0.38 g, 2.57mmol) and (S)-2-hydroxy-propionic acid (S)-1-benzyloxycarbonyl-ethylester (1-2) (0.5 g, 1.98 mmol) in dichloromethane (10 mL) was addedEDCI.HCl (0.57 g, 2.97 mmol) and 4-dimethylaminopyridine (24 mg, 0.19mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for1 hour. The resulting reaction mixture was quenched with water (50 mL),extracted with dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% ethyl acetate in hexane) to afford product 15-2 as apale yellow liquid (450 mg, 60%). ¹H NMR (400 MHz, Chloroform-d) δ7.42-7.29 (m, 5H), 5.26-5.09 (m, 4H), 4.20 (q, J=6.9 Hz, 1H), 1.53 (d,J=7.1 Hz, 6H), 1.40 (d, J=6.8 Hz, 3H), 1.22 (s, 9H); MS m/z (M+NH₄ ⁺)398.2.

Step 2: (S)-2-tert-Butoxy-propionic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester (15-3)

A solution of (S)-2-tert-butoxy-propionic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester (15-2) (450mg, 1.18 mmol) in methanol (10 mL) and 10% Pd/C (50 mg, 50% wet) wereadded to a 100 mL autoclave vessel at 25-30° C. The reaction mixture wasstirred at room temperature under hydrogen pressure (5 kg/cm²) for 2hours. After completion of the reaction, the reaction mixture wasfiltered through celite. Evaporation of volatiles under reduced pressureafforded product 15-3 as a pale yellow liquid (290 mg, 84%). ¹H NMR (400MHz, DMSO-d₆) δ 5.07 (q, J=7.0 Hz, 1H), 4.90 (q, J=7.0 Hz, 1H), 4.23 (q,J=6.8 Hz, 1H), 1.41 (dd, J=32.0, 7.1 Hz, 6H), 1.23 (d, J=6.8 Hz, 3H),1.12 (s, 9H); MS m/z (M−H) 289.0.

Step 1: Octadecanoic acid (S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester (16-2)

To a solution of octadecanoic acid (16-1) (23.4 g, 82.53 mmol) and(S)-2-hydroxy-propionic acid (S)-1-benzyloxycarbonyl-ethyl ester(1-2)(16.0 g, 63.49 mmol) in dichloromethane (160 mL) was added EDCI.HCl(24.2 g, 126.9 mmol) and 4-dimethylaminopyridine (770 mg, 6.34 mmol) at0° C. The reaction mixture was allowed to stir at 25-30° C. for 1 hour,and the resulting reaction mixture was quenched with water (500 mL),extracted with dichloromethane (500×3 mL), dried over sodium sulfate,and concentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (2% ethyl acetate in hexane) to afford product 16-2 as apale yellow liquid (18 g, 55%). ¹H NMR (400 MHz, DMSO-d₆) 7.43-7.30 (m,5H), 5.17-5.14 (m, 3H), 5.03 (q, J=7.2 Hz, 1H), 2.32 (t, J=7.3 Hz, 2H),1.55-1.41 (m, 2H), 1.36 (d, J=7.1 Hz, 3H), 1.26 (d, J=6.1 Hz, 3H),1.21-1.22 (m, 26H), 0.89 (t, J=6.4 z, 3H); MS m/z (M+NH₄ ⁺⁾ 536.7.

Step 2: Octadecanoic acid (S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethylester (16-3)

A solution of octadecanoic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester (16-2) (18 g,34.74 mmol) in methanol (90 mL) and 10% Pd/C (3.6 g, 50% wet) were addedto a 500 mL autoclave vessel at 25-30° C. The reaction mixture wasstirred at room temperature under hydrogen pressure (5 kg/cm²) over aperiod of 2 hours, and after completion of the reaction, the reactionmixture was filtered through celite. Evaporation of volatiles underreduced pressure afforded product 16-3 as a colorless low melting solid(12.5 g, 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 5.01 (dq,J=25.2, 7.0 Hz, 2H), 2.33 (t, J=7.3 Hz, 2H), 1.57-1.47 (m, 2H), 1.42 (t,J=6.7 Hz, 6H), 1.23-1.20 (m, 30H), 0.89-0.81 (m, 3H); MS m/z (M+NH₄ ⁺)446.7.

Step 3: Octadecanoic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (16-4)

To a solution of octadecanoic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester (16-3) (10.2 g, 23.80mmol) and (S)-2-hydroxy-propionic acid (S)-1-benzyloxycarbonyl-ethylester (1-2) (4.0 g, 15.87 mmol) in dichloromethane (40 mL) was addedEDCI.HCl (6.06 g, 31.74 mmol), hydroxybenzotriazole (428 mg, 3.174mmol), and 4-dimethylaminopyridine (193 mg, 1.58 mmol) and at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour. Theresulting reaction mixture was quenched with water (500 mL), extractedwith dichloromethane (500×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (3% ethyl acetate in hexane) to afford product 16-4 as apale yellow liquid (6.1 g, 58%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.43-7.32(m, 5H), 5.19-5.04 (m, 6H), 2.31-2.35 (m, 2H), 1.55-1.50 (m, 2H),1.46-1.40 (m, 12H), 1.23-1.22 (m, 28H), 0.89-0.81 (m, 3H); MS m/z (M+NH₄⁺) 680.4.

Step 4: Octadecanoic acid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethyl ester (16-5)

A solution of octadecanoic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (16-4) (6.1 g, 9.21 mmol) in methanol (40 mL) and 10% Pd/C (1.2 g,50% wet) were added to a 250 mL autoclave vessel at 25-30° C. Thereaction mixture was stirred at room temperature under hydrogen pressure(5 kg/cm²) for 2 hours. After completion of the reaction, the reactionmixture was filtered through celite. Evaporation of volatiles underreduced pressure afforded product 16-5 as a colorless low melting solid(4.5 g, 85%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.2 (bs, 1H), 5.18 (qd,J=7.0, 2.4 Hz, 2H), 5.02 (dq, J=28.5, 7.0 Hz, 2H), 2.33 (t, J=7.3 Hz,2H), 1.55-1.28 (m, 14H), 1.28 (m, 28H), 0.89-0.81 (m, 3H); MS m/z (M−H)571.5.

Step 1: Octadecanoic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl)}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (17-1)

To a solution of octadecanoic acid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (16-5) (16.2 g, 28.37 mmol) and (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (5.5 g, 21.82 mmol) indichloromethane (55 mL) was added EDCI.HCl (8.33 g, 43.64 mmol),hydroxybenzotriazole (602 mg, 4.36 mmol), and 4-dimethylaminopyridine(266 mg, 2.18 mmol) at 0° C. The reaction mixture was allowed to stir at25-30° C. for 1 hour. The resulting reaction mixture was quenched withwater (500 mL), extracted with dichloromethane (500×3 mL), dried oversodium sulfate, and concentrated under reduced pressure. The crudeproduct obtained upon evaporation of volatiles was purified by silicagel (230-400) column chromatography (3% ethyl acetate in hexane) toafford product 17-1 as a pale yellow liquid (13.5 g, 76%). ¹H NMR (400MHz, DMSO-d₆) δ 7.43-7.32 (m, 5H), 5.25-5.13 (m, 7H), 5.01-5.00 (m, 1H),2.31-2.35 (m, 2H), 1.53-1.37 (m, 20H), 1.25-1.23 (m, 28H), 0.89-0.81 (m,3H); MS m/z (M+NH₄ ⁺) 824.9.

Step 2: Octadecanoic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (17-2)

A solution of octadecanoic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (17-1) (13.5 g, 16.74 mmol) in methanol (80 mL) and 10% Pd/C (2.7g, 50% wet) To a 250 mL autoclave vessel at 25-30° C. The reactionmixture was stirred at room temperature under hydrogen pressure (5kg/cm²) for 2 hours. After completion of the reaction, the reactionmixture was filtered through celite. Evaporation of volatiles underreduced pressure afforded product 17-2 as a colorless low melting solid(9.8 g, 81%). ¹H NMR (400 MHz, DMSO-d₆) δ 5.25-5.13 (m, 4H), 5.06 (dq,J=27.5, 7.0 Hz, 1H), 5.02 (dq, J=27.5, 7.0 Hz, 1H), 2.33 (t, J=7.3 Hz,2H), 1.55-1.36 (m, 18H), 1.26 (m, 30H), 0.89-0.81 (m, 3H); MS m/z (M−H)715.7.

Step 1:(2S)-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-(Benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy})-1-oxopropan-2-yloctadecanoate (18-1)

To a solution of octadecanoic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (17-2) (4.2 g, 6.19 mmol) and (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (1.2 g, 4.76 mmol) indichloromethane (15 mL) was added EDCI.HCl (1.01 g, 9.52 mmol),hydroxybenzotriazole (131 mg, 0.95 mmol), and 4-dimethylaminopyridine(58 mg, 0.47 mmol) and at 0° C. The reaction mixture was allowed to stirat 25-30° C. for 1 hour. The resulting reaction mixture was quenchedwith water (100 mL), extracted with dichloromethane (150×3 mL), driedover sodium sulfate, and concentrated under reduced pressure. The crudeproduct obtained upon evaporation of volatiles was purified by silicagel (230-400) column chromatography (12% ethyl acetate in hexane) toafford product 18-1 as a pale yellow liquid (3.5 g, 77%). 1H NMR (400MHz, DMSO-d₆) δ 7.41-7.32 (m, 5H), 5.25-5.13 (m, 9H), 5.01-5.02 (m, 1H),2.33 (t, J=7.3 Hz, 2H), 1.53-1.37 (m, 24H), 1.26-1.22 (m, 30H),0.89-0.79 (m, 3H); MS m/z (M+NH₄) 969.0.

Step 2: Octadecanoic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (18-2)

A solution of(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-(benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yloctadecanoate (18-1) (3.5 g, 3.68 mmol) in methanol (20 mL) and 10% Pd/C(0.7 g, 50% wet) were added to a 100 mL autoclave vessel at 25-30° C.The reaction mixture was stirred at room temperature under hydrogenpressure (5 kg/cm²) over a period of 2 hours. After completion of thereaction, the reaction mixture was filtered through celite. Evaporationof volatiles under reduced pressure afforded product 18-2 as a colorlesslow melting solid (2.5 g, 79%). 1H NMR (400 MHz, DMSO-d₆) δ13.2 (bs,1H), 5.26-5.13 (m, 6H), 5.08 (q, J=6.8 Hz, 1H), 5.01 (q, J=6.8 Hz, 1H),2.33 (t, J=7.3 Hz, 2H), 1.55-1.36 (m, 26H), 1.32-1.23 (m, 30H),0.89-0.81 (m, 3H); MS m/z (M+NH₄+) 879.0.

Example 2. Synthetic Examples of Dorzolmide Mono-Prodrugs

Step 1:(2S)-2-[(tert-Butyldiphenylsilyl)oxy]-N-{[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}propanamide(19-2)

To a solution of dorzolamide (19-1) (0.8 g, 2.22 mmol) indichloromethane (10 mL) was added N,N-diisopropylethylamine (0.8 mL,4.44 mmol) at 0° C. After 30 minutes,(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid (14-2) (1.01 g,3.33 mmol), EDCI.HCl (0.763 g, 3.99 mmol), and 4-dimethylaminopyridine(0.027 g, 0.22 mmol) were added at 0° C. The reaction mixture wasallowed to stir at 25-30° C. for 1 hour, and the resulting reactionmixture was quenched with water (100 mL), extracted with dichloromethane(200×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (230-400) column chromatography (6% methanol inDCM) to afford product 19-2 as a pale yellow solid (1.3 g, 68%). ¹H NMR(400 MHz, DMSO-d₆) δ 8.78 (bs, 2H), 7.71 (s, 1H), 7.65-7.61 (m, 4H),7.45-7.31 (m, 6H), 4.64 (b s, 1H), 3.97 (q, J=6.8, 2H), 3.20 (bs, 1H),3.01 (bs, 1H), 1.37 (d, J=6.8, 3H), 1.23-1.02 (m, 8H), 0.98 (s, 9H); MSm/z (M−H) 633.5; MS m/z (M+H) 635.3.

Step 2:(2S)—N-{[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}-2-hydroxypropanamide(19-3)

To a solution of(2S)-2-[(tert-butyldiphenylsilyl)oxy]-N-{[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}propanamide(19-2) (1.3 g, 2.50 mmol) in tetrahydrofuran (15 mL) were addedtetra-butyl ammonium fluoride (3.07 mL, 1.0M, 3.07 mmol) and acetic acid(0.18 g, 3.07 mmol) at 0° C. The reaction mixture was allowed to stir atroom temperature for 12 hours, and the resulting reaction mixture wasconcentrated under reduced pressure. The crude product obtained uponevaporation of the volatiles was purified by silica gel columnchromatography (5% methanol in ethyl acetate) to afford product 19-3 asan off-white solid (510 mg, 63%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.39 (s,1H), 4.00 (d, J=5 Hz 1H), 3.95-3.80 (m, 2H), 3.73 (quintet, 1H),2.70-2.45 (m, 2H), 2.36-2.20 (m, 2H), 1.32 (d, 3H), 1.12 (d, 3H), 1.02(t, 3H); MS m/z (M+H)⁺ 397.1.

Step 1:(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (20-1)

To a solution of dorzolamide 19-1 (0.8 g, 2.22 mmol) in dichloromethane(10 mL) was added N,N-diisopropylethylamine (0.8 mL, 4.44 mmol) at 0° C.After 30 minutes, 2-(tert-butyl-diphenyl-silanyloxy)-propionic acid1-(1-carboxy-ethoxycarbonyl)-ethyl ester (2-3) (1.01 g, 3.33 mmol),EDCI.HCl (0.763 g, 3.99 mmol) and 4-dimethylaminopyridine (0.027 g, 0.22mmol) were added at 0° C. The reaction mixture was allowed to stir at25-30° C. for 1 hour, and the resulting reaction mixture was quenchedwith water (100 mL), extracted with dichloromethane (200×3 mL), driedover sodium sulfate, and concentrated under reduced pressure. The crudeproduct obtained upon evaporation of volatiles was purified by silicagel (230-400) column chromatography (6% methanol in DCM) to affordproduct 20-1 as a pale yellow solid (1.3 g, 68%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.6-7.40 (m, 11H), 4.9-4.7 (m, 2H), 4.3 (q, J=6.8 Hz. 1H),4.0-3.8 (m, 2H), 3.6-3.5 (m, 1H), 3.3-3.1 (m, 1H), 2.8-2.6 (m, 2H),2.4-2.2 (m, 2H), 1.4-1.2 (m, 16H), 1.02 (s, 9H); MS m/z (M+H) 779.4.

Step 2:(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (20-2)

To a solution of(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (20-1) (1.0 g, 1.28mmol) in tetrahydrofuran (15 mL) were added tetra-butyl ammoniumfluoride (2.56 mL, 1.0 M, 2.56 mmol) and acetic acid (0.15 g, 2.56 mmol)at 0° C. The reaction mixture was allowed to stir at room temperaturefor 12 hours, and the resulting reaction mixture was concentrated underreduced pressure. The crude product obtained upon evaporation of thevolatiles was purified by silica gel column chromatography (4% methanolin ethyl acetate) to afford product 20-2 as an off-white solid (400 mg,57%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H), 5.41 (d, 1H), 5.02 (q,J=7.1 Hz, 1H), 4.79 (q, J=7.1 Hz, 1H), 4.18 (quintet, J=7.1 Hz, 1H),3.95-3.75 (m, 2H), 2.70-2.45 (m, 2H), 2.35-2.20 (m, 2H), 1.48 (d, 2H),1.36-1.24 (m, 9H), 1.02 (t, 3H); MS m/z (M+H)⁺ 540.6.

Step 1:(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (21-1)

To a solution of dorzolamide (19-1) (1.0 g, 2.7 mmol) in dichloromethane(10 mL) was added N,N-diisopropylethylamine (0.96 mL, 5.5 mmol) at 0° C.After 30 minutes, (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethyl ester(3-2) (2.27 g, 4.1 mmol), EDCI.HCl (0.79 g, 4.1 mmol) and4-dimethylaminopyridine (33 g, 0.27 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (150 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) column (6%methanol in DCM) to afford product 21-1 as an off-white solid (1.5 g,65%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.60 (d, J=6.4, 4H), 7.59-7.39 (m,7H), 5.06 (q, J=7.2 Hz, 1H), 4.92 (q, J=6.8 Hz, 1H), 4.28 (q, J=6.8 Hz,1H), 3.8-4.0 (m, 2H), 3.6 (bs, 1H), 3.2 (bs, 1H), 1.46 (d, J=6.8, 3H),1.36-1.24 (m, 12H), 1.02 (m, 12H); MS m/z (M+H) 851.4

Step 2:(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (21-2)

To a solution of(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (21-1) (1.8 g, 2.11mmol) in tetrahydrofuran (20 mL) were added tetra-butyl ammoniumfluoride (4.23 mL, 1.0M, 4.22 mmol) and acetic acid (0.25 g, 4.22 mmol)at 0° C. The reaction mixture was allowed to stir at room temperaturefor 12 hours, and the resulting reaction mixture was concentrated underreduced pressure. The crude product obtained upon evaporation of thevolatiles was purified by silica gel column chromatography (4% methanolin ethyl acetate) to afford product 21-2 as an off-white solid (1.0 g,77%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.37 (s, 1H), 5.48 (d, J=5.6 Hz, 1H),5.0-5.15 (m, 2H), 4.79 (quintet, J=7.1 Hz, 1H), 4.25-4.15 (m, 1H),3.95-3.80 (m, 2H), 2.70-2.45-(m, 2H), 2.40-2.20-(m, 2H), 1.52-1.43 (m,6H), 1.36-1.24 (m, 9H), 1.02 (t, 3H); MS m/z (M+H)⁺ 613.2.

Step 1:(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate(22-1)

To a solution of dorzolamide (19-1) (1.0 g, 2.7 mmol) in dichloromethane(10 mL) was added N,N-diisopropylethylamine (0.96 mL, 5.5 mmol) at 0° C.After 30 minutes, (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester (4-2) (3.78 g, 4.1 mmol), EDCI.HCl (0.79 g, 4.1 mmol), and4-dimethylaminopyridine (33 g, 0.27 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (150 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% methanol in DCM) to afford product as 22-1 anoff-white solid (1.6 g, 63%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.60 (d,J=6.8, 4H), 7.51-7.40 (m, 7H), 5.17 (q, J=7.2 Hz, 2H), 5.07 (q, (q,J=6.8 Hz, 1H), 4.92 (q, J=7 Hz, 1H), 4.78 (q, J=6.8, 1H), 3.89 (m, 1H),3.1-3.2 (m, 1H), 2.9-2.7 (m, 1H), 3.12-3.10 (m, 1H), 1.48-1.40 (m, 6H),1.35-1.18 (m, 14H), 1.17-1.02 (m, 12H).

Step 2:(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (22-2)

To a solution of(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy})-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate(22-1) (1.0 g, 1.06 mmol) in tetrahydrofuran (10 mL) were addedtetra-butyl ammonium fluoride (2.1 mL, 1.0M, 2.12 mmol) and acetic acid(0.12 g, 2.12 mmol) at 0° C. The reaction mixture was allowed to stir atroom temperature for 12 hours, and the resulting reaction mixture wasconcentrated under reduced pressure. Crude product obtained uponevaporation of the volatiles was purified by silica gel columnchromatography (4% methanol in ethyl acetate) to afford product 22-2 asan off-white solid (200 mg, 27%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.75 (bs,2H), 7.71 (s, 1H), 5.47 (d, J=5.6 Hz, 1H), 5.20-5.07 (m, 3H), 4.81 (q,J=7 Hz, 1H), 4.61 (br, 1H), 4.21 (quintet, 1H), 4.15-4.25 (m, 1H),4.00-3.90 (m, 1H), 3.3-2.9 (m, 2H), 2.6-2.5 (m, 2H), 1.52-1.40 (m, 9H),1.36 (d, 3H), 1.35-1.22 (m, 6H), 1.17 (t, 3H). MS m/z (M+H)⁺ 685.2.

Step 1:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropanan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (23-1)

To a solution of dorzolamide (19-1) (0.35 g, 0.97 mmol) indichloromethane (10 mL) was added N,N-diisopropylethylamine (0.25 mL,1.94 mmol) at 0° C. After 30 minutes,(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-[(tertbutyldiphenylsilyl)oxy]propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoicacid (7-3) (1.42 g, 1.46 mmol), EDCI.HCl (0.37 g, 1.94 mmol), and4-dimethylaminopyridine (12 mg, 0.097 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (150 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (5% methanol in DCM) to afford product 23-1 as anoff-white solid (0.9 g, 72%).

Step 2:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (23-2)

To a solution of(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (23-1) (1.0 g, 1.06mmol) in tetrahydrofuran (10 mL) was added tetra-butyl ammonium fluoride(1.17 mL, 1.0M, 1.17 mmol) and acetic acid (0.07 g, 1.17 mmol) at 0° C.The reaction mixture was allowed to stir at room temperature for 12hours, and the resulting reaction mixture was concentrated under reducedpressure. The crude product obtained upon evaporation of the volatileswas purified by silica gel column chromatography (3% methanol in ethylacetate) to afford product 23-2 as an off-white solid (350 mg, 42%).¹H-NMR (400 MHz, DMSO-d₆) δ 8.75 (bs, 2H), 7.72 (s, 1H), 5.49 (d, J=6Hz, 1H), 5.24-5.05 (m, 8H), 4.80 (q, 1H), 4.63 (brs, 1H), 4.21 (quintet,1H), 4.0-3.9 (m, 1H), 3.3-3.12 (m, 1H), 3.08-2.91 (m, 1H), 2.5-2.6 (m,2H), 1.53-1.42 (m, 27H), 1.36 (d, 3H), 1.33-1.26 (m, 6H), 1.21 (t, 3H);MS m/z (M+H)⁺ 1045.6.

Step 1:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (24-1)

To a solution of dorzolamide (1.2 g, 3.32 mmol) in dichloromethane (20mL) was added N,N-diisopropylethylamine (0.84 mL, 6.64 mmol) at 0° C.After 30 minutes,(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-[(tertbutyldiphenylsilyl)oxy]propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoicacid (8-3) (5.5 g, 4.96 mmol), EDCI.HCl (1.26 g, 6.64 mmol), and4-dimethylaminopyridine (40 mg, 0.32 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (400 mL), extractedwith dichloromethane (300×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (4% methanol in DCM) to afford product as an off-whitesolid (4.0 g, 84%).

Step 2:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (24-2)

To a solution of(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (24-1) (3.9 g, 2.73mmol) in tetrahydrofuran (40 mL) were added tetra-butyl ammoniumfluoride (4.09 mL, 1.0M, 4.09 mmol) and acetic acid (0.24 g, 4.09 mmol)at 0° C. The reaction mixture was allowed to stir at room temperaturefor 12 hours, and the resulting reaction mixture was concentrated underreduced pressure. Crude product obtained upon evaporation of thevolatiles was purified by silica gel column chromatography (2% methanolin ethyl acetate) to afford product 24-2 as an off-white solid (2.3 g,70%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.75 (bs, 2H), 7.72 (s, 1H), 5.49 (d,J=6 Hz, 1H), 5.24-5.07 (m, 10H), 4.81 (q, 1H), 4.68-4.60 (m, 1H), 4.21(quintet, 1H), 4.0-3.9 (m, 1H), 3.3-3.12 (m, 1H), 3.08-2.91 (m, 1H),2.65-2.5 (m, 2H), 1.52-1.42 (m, 30H), 1.36 (d, 3H), 1.33-1.25 (m, 6H),1.20 (t, 3H); MS m/z (M+H)⁺1190.0.

Step 1:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (25-1)

To a solution of dorzolamide (0.3 g, 0.83 mmol) in dichloromethane (10mL) was added N,N-diisopropylethylamine (0.29 mL, 1.66 mmol) at 0° C.After 30 minutes,(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoicacid (9-3) (1.58 g, 1.25 mmol), EDCI.HCl (0.31 g, 1.66 mmol), and4-dimethylaminopyridine (10 mg, 0.08 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (150 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (4% methanol in DCM) to afford product 25-1 as anoff-white solid (1.1 g, 84%).

Step 2:(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy})-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy})-1-oxopropan-2-yl]oxy})-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (25-2)

To a solution of(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy})-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (25-1) (1.1 g, 0.69mmol) in tetrahydrofuran (15 mL) were added tetra-butyl ammoniumfluoride (1.04 mL, 1.0M, 1.04 mmol) and acetic acid (0.062 g, 1.04 mmol)at 0° C. The reaction mixture was allowed to stir at room temperaturefor 12 hours, and the resulting reaction mixture was concentrated underreduced pressure. Crude product obtained upon evaporation of thevolatiles was purified by silica gel column chromatography (2% methanolin ethyl acetate) to afford product 25-2 as an off-white solid (0.5 g,53%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.75 (bs, 2H), 7.71 (s, 1H), 5.48 (d,J=6 Hz, 1H), 5.25-5.07 (m, 12H), 4.81 (q, 1H), 4.63 (bs, 1H), 4.20(quintet, 1H), 4.0-3.9 (m, 1H), 3.30-3.12 (m, 1H), 3.08-2.90 (m, 1H),1.50-1.40 (m, 36H), 1.36 (d, 3H), 1.34-1.24 (m, 6H), 1.20 (t, 3H); MSm/z (M+H)⁺ 1333.8.

To a solution of dorzolamide (19-1) (0.2 g, 0.55 mmol) indichloromethane (5 mL) was added N,N-diisopropylethylamine (0.2 mL, 1.11mmol) at 0° C. After 30 minutes,(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-4) (0.23 g, 0.83 mmol), EDCI.HCl (159 mg, 0.83 mmol), and4-dimethylaminopyridine (6 mg, 0.05 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% methanol in DCM) to afford product 26-1 as a paleyellow solid (100 mg, 31%). ¹H-NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 5.14(q, J=7 Hz, 1H), 5.06 (q, J=7 Hz, 1H), 4.91 (q, J=7 Hz, 1H), 3.99 (br,1H), 3.90-3.75 (m, 1H), 2.80-2.68 (m, 2H), 2.5-2.3 (m, 2H), 2.12 (s,3H), 1.56-1.44 (m, 9H), 1.40 (d, 3H), 1.11 (t, 3H); MS m/z (M+H)⁺ 583.2.

To a solution of dorzolamide (19-1) (0.5 g, 1.38 mmol) indichloromethane (10 mL) was added N,N-diisopropylethylamine (0.5 mL,2.77 mmol) at 0° C. After 30 minutes,(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionicacid (11-4) (0.72 g, 2.08 mmol), EDCI.HCl (530 mg, 2.77 mmol), and4-dimethylaminopyridine (16 mg, 0.13 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour, and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% methanol in DCM) to afford product 27-1 as a paleyellow solid (250 mg, 26%). ¹H-NMR (400 MHz, MeOH-d₄) δ 7.70 (s, 1H),5.21-5.10 (m, 2H), 5.06 (q, 1H), 4.65-4.55 (br, 1H), 3.86-3.74 (m, 1H),3.20-3.05 (m, 2H), 2.74-2.54 (m, 2H), 2.08 (s, 3H), 1.58-1.45 (m, 12H),1.42 (d, 3H), 1.32 (t, 3H); MS m/z (M+H)⁺ 655.2.

To a solution of dorzolamide (0.5 g, 1.38 mmol) in dichloromethane (10mL) was added N,N-diisopropylethylamine (0.5 mL, 2.77 mmol) at 0° C.After 30 minutes,(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionicacid (12-2) (0.87 g, 2.08 mmol), EDCI.HCl (530 mg, 2.77 mmol), and4-dimethylaminopyridine (16 mg, 0.13 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% methanol in dichloromethane) to afford product 28-1as a pale yellow solid (390 mg, 38%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.75(bs, 2H), 7.72 (s, 1H), 5.15-5.22 (m, 2H), 5.13-5.01 (m, 2H), 4.81 (q,J=7 Hz, 1H), 4.68-4.55 (m, 1H), 4.00-3.90 (m, 1H), 3.27-3.14 (m, 1H),3.07-2.92 (m, 1H), 2.6-2.5 (m, 2H), 2.07 (s, 3H), 1.53-1.40 (m, 12H),1.34 (d, 3H), 1.28 (d, 3H), 1.18 (t, 3H). MS m/z (M+H)⁺ 727.8.

To a solution of dorzolamide (19-1) (0.3 g, 0.833 mmol) indichloromethane (5 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.66mmol) at 0° C. After 30 minutes,(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionyloxy]-propionicacid (13-2) (0.615 g, 1.25 mmol), EDCI.HCl (286 mg, 1.49 mmol), and4-dimethylaminopyridine (10 mg, 0.083 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% methanol in DCM) to afford product 29-1 as anoff-white solid (130 mg, 20%). ¹H-NMR (400 MHz, MeOH-d₄) δ 7.73 (s, 1H),5.21-5.12 (m, 4H), 5.06 (q, 1H), 4.88 (q, 1H), 4.60 (br, 1H), 3.75-3.86(m, 1H), 3.10-3.23 (m, 2H), 2.76-2.56 (m, 2H), 2.09 (s, 3H), 1.58-1.45(m, 18H), 1.41 (d, 3H), 1.32 (t, 3H); MS m/z (M+H)⁺799.4.

To a solution of dorzolamide (19-1) (0.3 g, 0.833 mmol) indichloromethane (5 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.66mmol) at 0° C. After 30 minutes, octadecanoic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (17-2) (0.77 g, 1.08 mmol), EDCI.HCl (318 mg, 1.66 mmol), and4-dimethylaminopyridine (10 mg, 0.083 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (4% methanol in DCM) to afford product as an off-whitesolid (140 mg, 16%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.75 (bs, 2H), 7.72 (s,1H), 5.23-5.15 (m, 3H), 5.14-5.00 (m, 2H), 4.81 (q, 1H), 4.66-4.57 (m,1H), 4.00-3.93 (m. 1H), 3.30-2.94 (m, 2H), 2.7-2.4 (m, 2H), 2.32 (t,2H), 1.55-1.15 (m, 54H), 0.83 (t, 3H); MS m/z (M+H)⁺ 1023.9.

To a solution of dorzolamide (19-1) (0.3 g, 0.833 mmol) indichloromethane (5 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.66mmol) at 0° C. After 30 minutes, octadecanoic acid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (18-2) (1.07 g, 1.24 mmol), EDCI.HCl (318 mg, 1.66 mmol), and4-dimethylaminopyridine (10 mg, 0.083 mmol) were added at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (4% methanol in dichloromethane) to afford product 31-1as an off-white solid (350 mg, 36%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.75(bs, 2H), 7.72 (s, 1H), 5.25-5.14 (m, 5H), 5.14-5.01 (m, 2H), 4.81 (q,1H), 4.67-4.57 (m, 1H), 4.01-3.91 (m, 1H), 3.45-3.12 (m, 1H), 3.07-2.93(m, 1H), 2.7-2.4 (m, 2H), 2.31 (t, 2H), 1.55-1.15 (m, 60H), 0.82 (t,3H); MS m/z (M+H)⁺ 1168.4.

Example 3. Synthetic Examples of Brinzolmide Mono-Prodrugs

Step 1:(2S)-2-[(tert-Butyldiphenylsilyl)oxy]-N-{[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}propanamide(32-2)

To a solution of brinzolamide (32-1) (1 g, 2.61 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid (14-2) (1.71 g,5.22 mmol) in dichloromethane (10 mL) was added EDCI.HCl (0.99 g, 5.22mmol) and 4-dimethylaminopyridine (310 mg, 0.26 mmol) at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (200×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% methanol in DCM) to afford product as an off-whitesolid (1.1 g, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 9.01 (s,1H), 7.83 (s, 1H), 7.70-7.50 (m, 4H), 7.4-7.2 (m, 6H), 4.9 (s, 1H), 4.15(bs, 2H), 4.01 (q, J=7 Hz, 1H), 3.40 (s, 3H), 3.30 (s, 3H), 3.1 (s, 1H),1.79 (quintet, 2H), 1.33-1.18 (m, 3H), 1.01 (s, 3H), 0.98 (s, 9H); MSm/z (M+H) 694.4.

Step 2:(2S)—N-{[(4R)-4-(Ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}-2-hydroxypropanamide(32-3)

To a solution of(2S)-2-[(tert-butyldiphenylsilyl)oxy]-N-{[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}propanamide(32-2) (1.1 g, 1.19 mmol) in tetrahydrofuran (10 mL) were addedtetra-butyl ammonium fluoride (1.43 mL, 1.14 mmol) and acetic acid (0.18g, 3.01 mmol) at 0° C. The reaction mixture was allowed to stir at roomtemperature for 12 hours and the resulting reaction mixture wasconcentrated under reduced pressure. Crude product obtained uponevaporation of the volatiles was purified by silica gel columnchromatography (5% methanol in ethyl acetate) to afford product 32-3 asan off-white solid (0.45 g, 62%). ¹H-NMR (400 MHz, DMSO-d₆) δ 9.3-8.8(m, 2H), 7.83 (s, 1H), 4.90-4.75 (m, 1H), 4.12-3.96 (m, 3H), 3.77 (q,J=7 Hz, 1H), 3.41-3.34 (m, 3H), 3.23 (s, 3H), 3.22-3.12 (m, 1H),3.11-2.97 (m, 2H), 1.83 (quintet, 2H), 1.21 (t, 3H), 1.13 (t, 3H); MSm/z (M+H)⁺

Step 1:(1S)-1-({[(4R)-4-(Ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethyl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (33-1)

To a solution of brinzolamide (32-1) (0.1 g, 0.26 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-carboxy-ethyl ester (1-4) (0.17 g, 0.31 mmol) in dichloromethane(5 mL) was added EDCI.HCl (0.064 g, 0.33 mmol) and4-dimethylaminopyridine (3 mg, 0.026 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 1 hour and the resulting reactionmixture was quenched with water (30 mL), extracted with dichloromethane(50×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (230-400) column chromatography (6% methanol inDCM) to afford product 33-1 as an off-white solid (0.15 g, 65%).

Step 2:(1S)-1-({[(4R)-4-(Ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethyl(2S)-2-hydroxypropanoate (33-2)

To a solution of(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethyl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (33-1) (1.0 g, 1.19mmol) in tetrahydrofuran (10 mL) were added tetra-butyl ammoniumfluoride (1.43 mL, 1.0M, 1.14 mmol) and acetic acid (0.18 g, 3.01 mmol)at 0° C. The reaction mixture was allowed to stir at room temperaturefor 12 hours and the resulting reaction mixture was concentrated underreduced pressure. Crude product obtained upon evaporation of thevolatiles was purified by silica gel column chromatography (5% methanolin ethyl acetate) to afford product 33-2 as an off-white solid (450 mg,62%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.46 (s, 1H), 5.26 (d, 1H), 4.78 (q,J=7 Hz, 1H), 4.08 (quintet, J=7 Hz, 1H), 4.05-3.96 (m, 1H), 3.78-3.65(m, 2H), 3.43-3.30 (m, 3H), 3.22 (s, 3H), 3.17-3.10 (m, 1H), 2.6-2.5 (m,2H), 1.79 (quintet, 2H), 1.30-1.21 (m, 6H), 1.01 (t, 3H); MS m/z (M+H)⁺582.2.

Step 1:(2S)-1-[(1S)-1-({[(4R)-4-(Ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (34-1)

To a solution of brinzolamide (32-1) (0.8 g, 2.00 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester 2-3 (1.47 g, 3.10 mmol)in dichloromethane (10 mL) was added EDCI.HCl (0.59 g, 3.1 mmol) and4-dimethylaminopyridine (25 mg, 0.20 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 1 hour and the resulting reactionmixture was quenched with water (30 mL), extracted with dichloromethane(50×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (230-400) column chromatography (6% methanol indichloromethane) to afford product 34-1 as an off-white solid (1.3 g,76%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.60 (d, J=6.0, 4H), 7.59-7.40 (m,7H), 4.81 (q, J=7 Hz, 1H), 4.79 (q, J=7 Hz, 1H), 4.27 (q, J=6.8, 1H),3.76 (bs, 2H), 3.40-3.31 (m, 3H), 3.21 (s, 3H), 3.14-3.11 (m, 1H),2.67-2.66 (m, 1H), 1.79 (quintet, J=7 Hz, 2H), 1.33-1.27-(m, 9H), 1.22(s, 3H), 1.02 (s, 9H); MS m/z (M+H) 838.4

Step 2:(2S)-1-[(1S)-1-({[(4R)-4-(Ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (34-2)

To a solution of(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (34-1) (1.0 g, 1.19mmol) in tetrahydrofuran (10 mL) were added tetra-butyl ammoniumfluoride (1.43 mL, 1.0M, 1.14 mmol) and acetic acid (0.18 g, 3.01 mmol)at 0° C. The reaction mixture was allowed to stir at room temperaturefor 12 hours and the resulting reaction mixture was concentrated underreduced pressure. Crude product obtained upon evaporation of thevolatiles was purified by silica gel column chromatography (5% methanolin ethyl acetate) to afford product 34-2 as off-white solid (450 mg,62%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.47 (s, 1H), 5.44 (d, 1H), 5.01 (q,J=7 Hz, 1H), 4.79 (q, J=7 Hz, 1H), 4.18 (quintet, J=7 Hz, 1H), 4.05-3.96(m, 1H), 3.81-3.66 (m, 2H), 3.42-3.30 (m, 3H), 3.22 (s, 3H), 3.16-3.07(m, 1H), 2.6-2.5 (m, 2H), 1.78 (quintet, 2H), 1.47 (d, 3H), 1.33-1.21-\(m, 6H), 0.99 (t, 3H); MS m/z (M+H)⁺ 600.3.

Step 1:(2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(Ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (35-1)

To a solution of brinzolamide (32-1) (0.1 g, 2.61 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethyl ester(3-2) (0.17 g, 3.12 mmol) in dichloromethane (5 mL) was added EDCI.HCl(64 mg, 0.33 mmol), 4-dimethylaminopyridine (3 mg, 0.026 mmol) at 0° C.The reaction mixture was allowed to stir at 25-30° C. for 1 hour and theresulting reaction mixture was quenched with water (30 mL), extractedwith dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (4% methanol in dichloromethane) to afford product 35-1as an off-white solid (150 mg, 65%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.62(d, J=6.4 Hz, 4H), 7.48-7.39 (m, 7H), 5.06 (q, J=7.2 Hz, 1H), 4.92 (q,J=7.2, 1H), 4.77 (q, J=6.4 Hz, 1H), 4.29-4.27 (m, 1H), 3.77-3.64 (m,2H), 3.43-3.29 (m, 3H), 3.22 (s, 3H), 3.17-3.09 (m, 1H), 2.6-2.5 (m,2H), 1.79 (quintet, 2H), 1.43-1.50 (m, 3H), 1.30-1.24 (m, 9H), 1.00 (s,12H); MS m/z (M+H) 909.8

Step 2:(2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(Ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (35-2)

To a solution of(2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate (35-1) (250 mg, 0.27mmol) in tetrahydrofuran (5 mL) was added tetra-butyl ammonium fluoride(0.27 mL, 1.0M, 0.27 mmol) and acetic acid (0.032 g, 0.54 mmol) at 0° C.The reaction mixture was allowed to stir at room temperature for 12hours and the resulting reaction mixture was concentrated under reducedpressure. Crude product obtained upon evaporation of the volatiles waspurified by silica gel column chromatography (5% methanol in ethylacetate) to afford product 35-2 as off-white solid (130 mg, 72%). ¹H-NMR(400 MHz, DMSO-d₆) δ 7.47 (s, 1H), 5.47 (d, 1H), 5.13-5.04 (m, 2H), 4.79(q, 1H), 4.20 (quintet, 1H), 4.05-3.97 (m, 1H), 3.77-3.64 (m, 2H),3.43-3.29 (m, 3H), 3.22 (s, 3H), 3.17-3.09 (m, 1H), 2.6-2.5 (m, 2H),1.79 (quintet, 2H), 1.43-1.50 (m, 6H), 1.30-1.24 (m, 6H), 1.00 (t, 3H);MS m/z (M+H)⁺ 671.8.

To a solution of brinzolamide (32-1) (0.2 g, 0.52 mmol) and(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-4) (0.21 g, 0.78 mmol) in dichloromethane (5 mL) was added EDCI.HCl(150 mg, 0.78 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) at 0°C. The reaction mixture was allowed to stir at 25-30° C. for 1 hour andthe resulting reaction mixture was quenched with water (50 mL),extracted with dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (6% methanol in DCM) to afford product 36-1 as anoff-white solid (250 mg, 75%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.49 (s, 1H),5.11-4.99 (m, 2H), 4.79 (q, 1H), 4.11-3.95 (m, 1H), 3.80-3.64 (m, 2H),3.40-3.31 (m, 3H), 3.22 (s, 3H), 3.18-3.08 (m, 1H), 2.6-2.5 (m, 2H),2.06 (s, 3H), 1.80 (quintet, 2H), 1.48 (d, 3H), 1.42 (d, 3H), 1.29 (d,3H), 1.03 (t, 3H). MS m/z (M+H)⁺ 642.3.

To a solution of brinzolamide (32-1) (0.3 g, 0.78 mmol) and(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionicacid (11-4) (0.35 g, 1.01 mmol) in dichloromethane (10 mL) was addedEDCI.HCl (224 mg, 1.17 mmol) and 4-dimethylaminopyridine (9 mg, 0.07mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for1 hour and the resulting reaction mixture was quenched with water (50mL), extracted with dichloromethane (50×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (8% methanol in dichloromethane) toafford product 37-1 as an off-white solid (150 mg, 27%). ¹H-NMR (400MHz, DMSO-d₆) δ 9.11 (bs, 1H), 8.99 (bs, 1H), 7.81 (s, 1H), 5.02-5.20(m, 3H), 4.90-4.78 (m, 2H), 4.13-3.96 (m, 2H), 3.43-3.01 (m, 9H), 2.07(s, 3H), 1.82 (quintet, 2H), 1.51-1.40 (m, 9H), 1.30 (d, 3H), 1.21 (t,3H). MS m/z (M+H)⁺ 714.3.

To a solution of brinzolamide (32-1) (0.5 g, 1.30 mmol) and(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionicacid (12-2) (0.87 g, 2.08 mmol) in dichloromethane (5 mL) was addedEDCI.HCl (500 mg, 2.61 mmol), 4-dimethylaminopyridine (15 mg, 0.13 mmol)at 0° C. The reaction mixture was allowed to stir at 25-30° C. for 1hour and the resulting reaction mixture was quenched with water (50 mL),extracted with dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (8% methanol in DCM) to afford product 38-1 as anoff-white solid (260 mg, 26%). ¹H-NMR (400 MHz, DMSO-d₆) δ 9.12 (bs,1H), 8.98 (bs, 1H), 7.81 (s, 1H), 5.22-5.15 (m, 2H), 5.13-5.01 (m, 2H),4.90-4.77 (m, 2H), 4.12-3.92 (m, 2H), 3.41-3.34 (m, 3H), 3.22-2.96 (m,6H), 2.07 (s, 3H), 1.83 (quintet, 2H), 1.51-1.39 (m, 12H), 1.30 (d, 3H),1.21 (t, 3H); MS m/z (M+H)⁺ 786.6.

To a solution of brinzolamide (32-1) (0.3 g, 0.78 mmol) and(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionyloxy]-propionicacid 13-2 (0.57 g, 1.17 mmol) in dichloromethane (10 mL) was addedEDCI.HCl (268 mg, 1.40 mmol) and 4-dimethylaminopyridine (9 mg, 0.07mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for1 hour and the resulting reaction mixture was quenched with water (50mL), extracted with dichloromethane (50×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (6% methanol in dichloromethane) toafford product 39-1 as an off-white solid (220 mg, 32%). ¹H-NMR (400MHz, DMSO-d₆) δ 9.12 (bs, 1H), 8.99 (bs, 1H), 7.81 (s, 1H), 5.24-5.16(m, 3H), 5.13-5.01 (m, 2H), 4.90-4.77 (m, 2H), 4.15-3.92 (m, 2H),3.41-3.31 (m, 3H), 3.22-2.97 (m, 6H), 2.07 (s, 3H), 1.83 (quintet, 2H),1.52-1.40 (m, 15H), 1.30 (d, 3H), 1.21 (t, 3H); MS m/z (M+H)⁺ 858.4.

To a solution of brinzolamide (0.3 g, 0.78 mmol) and(S)-2-tert-butoxy-propionic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester (15-3) (0.29 g, 1.01mmol) in dichloromethane (10 mL) was added EDCI.HCl (224 mg, 1.17 mmol)and 4-dimethylaminopyridine (9 mg, 0.07 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. for 1 hour and the resultingreaction mixture was quenched with water (50 mL), extracted withdichloromethane (50×3 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (230-400) column chromatography (6%methanol in ethyl acetate) to afford product as 40-1 an off-white solid(125 mg, 24%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.49 (s, 1H), 5.01 (q, J=7Hz, 1H), 4.79 (q, J=7 Hz, 1H), 4.22 (q, J=7 Hz, 1H), 4.05-3.95 (m, 1H),3.82-3.65 (m, 2H), 3.43-3.33 (m, 3H), 3.22 (s, 3H), 3.18-3.08 (m, 1H),2.6-2.5 (m, 2H), 1.80 (quintet, 2H), 1.45 (d, 3H), 1.29 (d, 3H), 1.22(d, 3H), 1.11 (s, 9H), 1.02 (t, 3H); MS m/z (M+H)⁺ 656.3.

To a solution of brinzolamide (32-1) (0.35 g, 0.91 mmol) andoctadecanoic acid(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (17-2) (0.98 g, 1.37 mmol) in dichloromethane (5 mL) were addedEDCI.HCl (349 mg, 1.82 mmol) and 4-dimethylaminopyridine (11 mg, 0.09mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for1 hour and the resulting reaction mixture was quenched with water (30mL), extracted with dichloromethane (50×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (8% methanol in DCM) to afford product41-1 as an off-white solid (350 mg, (35%). ¹H-NMR (400 MHz, DMSO-d₆) δ9.12 (bs, 1H), 9.01 (bs, 1H), 7.84 (bs, 1H), 5.24-5.01 (m, 5H),4.90-4.75 (m, 2H), 4.15-3.90 (m, 2H), 3.41-3.30 (m, 3H), 3.24-2.90 (m,6H), 2.33 (t, 2H), 1.84 (quintet, 2H), 1.52-1.35 (m, 15H), 1.35-0.98 (m,36H), 0.81 (t, 3H); MS m/z (M+H)⁺ 1083.3.

To a solution of brinzolamide (32-1) (0.3 g, 0.78 mmol) and octadecanoicacid(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethoxycarbonyl)-ethylester (18-2) (1.01 g, 1.17 mmol) in dichloromethane (5 mL) was addedEDCI.HCl (300 mg, 1.56 mmol) and 4-dimethylaminopyridine (9 mg, 0.07mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for1 hour and the resulting reaction mixture was quenched with water (30mL), extracted with dichloromethane (50×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (8% methanol in DCM) to afford product42-1 as an off-white solid (245 mg, 25%). ¹H-NMR (400 MHz, DMSO-d₆) δ9.1 (bs, 2H), 7.82 (bs, 1H), 5.24-5.15 (m, 5H), 5.14-5.01 (m, 2H),4.83-4.73 (m, 2H), 4.15-3.90 (m, 2H), 3.41-3.30 (m, 3H), 3.24-2.85 (m,6H), 2.33 (t, 2H), 1.82 (quintet, 2H), 1.54-1.35 (m, 21H), 1.34-0.95 (m,36H), 0.82 (t, 3H). MS m/z (M+H)⁺ 1227.4.

Example 4. Synthetic Examples of Latanoprost Mono-Prodrugs

To a solution of lantanoprost (43-1) (0.1 g, 0.23 mmol) and(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-4) (0.22 g, 0.80 mmol) in dichloromethane (5 mL) was added EDCI.HCl(0.15 g, 0.00083 mol) and 4-dimethylaminopyridine (8 mg, 0.06 mmol) at0° C. The reaction mixture was allowed to stir at 25-30° C. for 48 hoursand the resulting reaction mixture was quenched with water (30 mL),extracted with dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (30% ethyl acetate in hexane) to afford product 43-2 as acolorless wax (100 mg, 37%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.29-7.22 (m,2H), 7.21-7.12 (m, 3H), 5.40-5.25 (m, 2H), 5.25-4.98 (m, 9H), 4.97-4.79(m, 4H), 2.21 (t, J=7 Hz, 2H), 2.19-2.07 (m, 2H), 2.06 (s, 9H),2.04-1.72 (m, 8H), 1.72-1.32 (m, 35H), 1.15 (d, 6H); MS m/z (M+H)⁺1207.8, (M+NH₄)+1224.8.

To a solution of lantanoprost (43-1) (0.1 g, 0.23 mmol) and(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionicacid (11-4) (0.35 g, 0.92 mmol) in dichloromethane (5 mL) was addedEDCI.HCl (0.176 g, 0.92 mmol) and 4-dimethylaminopyridine (14 mg, 0.11mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for28 hours and the resulting reaction mixture was quenched with water (30mL), extracted with dichloromethane (50×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (30% ethyl acetate in hexane) to affordproduct 44-1 as a colorless wax (200 mg, 60%). ¹H-NMR (400 MHz, DMSO-d₆)δ 7.29-7.22 (m, 2H), 7.19-7.12 (m, 3H), 5.39-5.25 (m, 2H), 5.25-4.98 (m,12H), 4.96-4.79 (m, 4H), 2.21 (t, J=7 Hz, 2H), 2.19-2.07 (m, 2H), 2.06(s, 9H), 2.05-1.72 (m, 8H), 1.72-1.33 (m, 44H), 1.15 (d, 6H); MS m/z(M+H)⁺ 1423.7, (M+NH₄)⁺ 1440.8.

To a solution of lantanoprost (43-1) (0.1 g, 0.23 mmol) and(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionicacid (12-2) (0.48 g, 0.11 mmol) in dichloromethane (5 mL) was addedEDCI.HCl (0.22 g, 1.15 mmol) and 4-dimethylaminopyridine (14 mg, 0.11mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for48 hours and the resulting reaction mixture was quenched with water (30mL), extracted with dichloromethane (50×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (30% ethyl acetate in hexane) to affordproduct 45-1 as a colorless wax (200 mg, 54%). ¹H-NMR (400 MHz, DMSO-d₆)δ 7.29-7.22 (m, 2H), 7.20-7.13 (m, 3H), 5.37-5.25 (m, 2H), 5.25-5.00 (m,15H), 4.94-4.77 (m, 4H), 2.21 (t, J=7 Hz, 2H), 2.19-2.07 (m, 2H), 2.06(s, 9H), 2.04-1.72 (m, 8H), 1.72-1.33 (m, 53H), 1.15 (d, 6H); MS m/z(M+NH₄)⁺ 1657.5.

To a solution of lantanoprost (43-1) (0.1 g, 0.23 mmol) and(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionyloxy]-propionicacid (13-2) (0.68 g, 0.13 mmol) in dichloromethane (5 mL) was addedEDCI.HCl (0.26 g, 1.13 mmol) and 4-dimethylaminopyridine (16 mg, 0.13mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for48 hours and the resulting reaction mixture was quenched with water (30mL), extracted with dichloromethane (50×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (30% ethyl acetate in hexane) to affordproduct 46-1 as a colorless wax (150 mg, 35%). ¹H-NMR (400 MHz, DMSO-d₆)δ 7.28-7.22 (m, 2H), 7.19-7.12 (m, 3H), 5.37-5.25 (m, 2H), 5.25-5.01 (m,18H), 4.94-4.78 (m, 4H), 2.21 (t, J=7 Hz, 2H), 2.19-2.07 (m, 2H), 2.06(s, 9H), 2.04-1.72 (m, 8H), 1.72-1.34 (m, 62H), 1.15 (d, 6H). MS m/z(M+NH₄)⁺ 1873.5.

Example 5. Synthetic Examples of Sunitinib Mono-Prodrugs

To a solution of5-[5-amino-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (0.6 g, 0.51 mmol) anddihydro-furan-2,5-dione (0.166 g, 1.66 mmol) in dichloromethane (12 mL)was added 4-dimethylaminopyridine (37 mg, 0.15 mmol) at 0° C. Afterstirring at room temperature for 6 hours, the resulting reaction mixturewas filtered to afford product 47-3 as a yellow solid (500 mg, 66%).¹H-NMR (400 MHz, DMSO-d₆) δ 13.64 (s, 1H), 10.83 (s, 1H), 10.09 (s, 1H),7.89 (s, 1H), 7.47-7.42 (m, 2H), 7.27-7.19 (dd, J=2 & 8 Hz, 1H), 6.80(d, J=8 Hz, 1H), 3.27 (q, J=6 Hz, 2H), 2.65-2.45 (m, 10H), 2.43, (s,3H), 2.39 (s, 3H), 0.97 (t, 6H). MS m/z (M+H)⁺ 496.4.

To a solution of 5-hydroxy-1,3-dihydro-indol-2-one (48-1) (3.37 g, 22.61mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (48-2) (6.0 g, 22.61 mol) in ethanol (120mL) was added piperidine (0.2 mL, 2.26 mmol) and the reaction mixturewas refluxed at 90° C. for 4 hours. The reaction mixture was thenconcentrated and washed with diethyl ether (25 mL) and ethyl acetate (25mL) to afford product 48-3 as an orange color solid (5.5 g, 61%). ¹H-NMR(400 MHz, DMSO-d₆) δ 13.71 (s, 1H), 10.59 (s, 1H), 8.91 (s, 1H), 7.49(s, 1H), 7.39 (t, 1H), 7.16 (d, J=2 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 6.56(dd, J=2 & 8 Hz, 1H), 3.29 (q, 2H), 2.6-2.5 (m, 6H), 2.45, (s, 3H), 2.43(s, 3H), 0.99 (t, 6H); MS m/z (M+H)⁺ 397.3.

To a solution of (S)-2-((S)-2-acetoxy-propionyloxy)-propionic acid(11-2) (0.388 g, 1.9 mmol) in dichloromethane (5 mL) was addedN,N-diisopropylethylamine (0.36 ml, 1.96 mmol), EDCI.HCl (0.363 g, 1.9mmol), 5-hydroxy Sunitinib (48-1) (0.3 g, 0.76 mmol), and4-dimethylaminopyridine (9 mg, 0.076 mmol) at 0° C. After stirring at25-30° C. for 3 hours, the reaction mixture was filtered andconcentrated under reduced pressure. The crude product obtained uponconcentration of volatiles was purified by preparative HPLC to affordproduct 49-1 as an orange color solid (0.13 g, 29%). ¹H-NMR (400 MHz,DMSO-d₆) δ 13.68 (s, 1H), 10.98 (s, 1H), 7.71 (s, 1H), 7.65 (d, J=2 Hz,1H), 7.49 (t, 1H), 6.89 (d, J=8 Hz, 1H), 6.83 (dd, J=2 & 8 Hz, 1H), 5.38(q, J=7 Hz, 1H), 5.10 (q, J=7 Hz, 1H), 2.7-2.5 (m, 6H), 2.44, (s, 3H),2.42 (s, 3H), 2.09 (s, 3H), 1.64 (d, J=7 Hz, 3H), 1.46 (d, J=7 Hz, 3H),0.99 (t, 6H); MS m/z (M+H)⁺ 583.4.

To a solution of(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionic acid(10-4) (0.52 g, 1.9 mmol) in dichloromethane (5 mL) was addedN,N-diisopropylethylamine (0.36 ml, 1.96 mmol), EDCI.HCl (0.363 g, 1.9mmol), 5-hydroxy Sunitinib (48-3) (0.3 g, 0.76 mmol) and4-dimethylaminopyridine (9 mg, 0.076 mmol) at 0° C. After stirring at25-30° C. for 3 hours, the reaction mixture was filtered andconcentrated under reduced pressure. The crude product obtained uponconcentration of volatiles was purified by preparative HPLC to affordproduct 50-1 as an orange color solid (0.15 g, 30%). ¹H-NMR (400 MHz,DMSO-d₆) δ 13.68 (s, 1H), 10.98 (s, 1H), 7.71 (s, 1H), 7.65 (d, J=2 Hz,1H), 7.49 (t, J=6 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 6.84 (dd, J=2 & 8 Hz,1H), 5.40 (q, J=7 Hz, 1H), 5.25 (q, J=7 Hz, 1H), 5.07 (q, J=7 Hz, 1H),3.31 (q, J=6 Hz, 2H), 2.69-2.50 (m, 6H), 2.45, (s, 3H), 2.42 (s, 3H),2.07 (s, 3H), 1.64 (d, J=7 Hz, 3H), 1.50 (d, J=7 Hz, 3H), 1.46 (d, J=7Hz, 3H), 0.99 (t, 6H); MS m/z (M+H)⁺ 655.4.

To a solution of(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy})-propionicacid (11-4) (0.65 g, 1.89 mmol) in dichloromethane (5 mL) was addedN,N-diisopropylethylamine (0.36 ml, 1.96 mmol), EDCI.HCl (0.363 g, 1.9mmol), 5-hydroxy Sunitinib (48-3) (0.3 g, 0.76 mmol), and4-dimethylaminopyridine (9 mg, 0.076 mmol) at 0° C. After stirring at25-30° C. for 3 hours, the reaction mixture was filtered andconcentrated under reduced pressure. The crude product obtained uponconcentration of volatiles was purified by preparative HPLC to affordproduct 51-1 as an orange color solid (0.13 g, 23%). ¹H-NMR (400 MHz,DMSO-d₆) δ 13.68 (s, 1H), 10.98 (s, 1H), 7.70 (s, 1H), 7.65 (d, J=2 Hz,1H), 7.46 (t, 1H), 6.89 (d, J=8 Hz, 1H), 6.83 (dd, J=2 & 8 Hz, 1H), 5.41(q, J=7 Hz, 1H), 5.26 (q, J=7 Hz, 1H), 5.22 (q, J=7 Hz, 1H), 5.05 (q,J=7 Hz, 1H), 2.69-2.5 (m, 6H), 2.44, (s, 3H), 2.42 (s, 3H), 2.07 (s,3H), 1.64 (d, J=7 Hz, 3H), 1.51-41 (m, 9H), 0.98 (t, 6H); MS m/z (M+H)⁺727.5.

To a solution of(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxy-propionyloxy)-propionyloxy]-propionyloxy}-propionyloxy)-propionicacid (12-2) (0.79 g, 1.89 mmol) in dichloromethane (5 mL) was addedN,N-diisopropylethylamine (0.36 ml, 1.96 mmol), EDCI.HCl (0.363 g, 1.9mmol), 5-hydroxy Sunitinib (48-3) (0.3 g, 0.76 mmol), and4-dimethylaminopyridine (9 mg, 0.076 mmol) at 0° C. After stirring at25-30° C. for 3 hours, the reaction mixture was filtered andconcentrated under reduced pressure. The crude product obtained uponconcentration of volatiles was purified by preparative HPLC to affordproduct 52-1 as an orange color solid (0.24 g, 40%). ¹H-NMR (400 MHz,DMSO-d₆) δ 13.68 (s, 1H), 10.98 (s, 1H), 7.70 (s, 1H), 7.65 (d, J=2 Hz,1H), 7.45 (t, 1H), 6.89 (d, J=8 Hz, 1H), 6.83 (dd, J=2 & 8 Hz, 1H), 5.41(q, J=7 Hz, 1H), 5.30-5.17 (m, 3H), 5.05 (q, J=7 Hz, 1H), 3.35-3.2 (m,2H), 2.6-2.5 (m, 6H), 2.44, (s, 3H), 2.42 (s, 3H), 2.06 (s, 3H), 1.64(d, J=7 Hz, 3H), 1.52-40 (m, 12H), 0.98 (t, 6H). MS m/z (M+H)⁺ 799.6.

(2S)-1-{[(2S)-1-{[(3Z)-3-[(4-{[2-(Diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (53-2)

Step 1: (S)-2-(tert-Butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yloxycarbonyl}-ethoxycarbonyl)-ethylester (53-1)

To a solution of 5-hydroxy Sunitinib (48-3) (0.2 g, 0.50 mmol) and(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester (2-3) (0.35 g, 0.75mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine(0.2 mL, 1.109 mmol) HATU (0.310 g, 0.80 mmol), and4-dimethylaminopyridine (3 mg, 0.026 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 2 hours and the resulting reactionmixture was quenched with water (30 mL), extracted with dichloromethane(50×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (230-400) column chromatography (4% methanol inDCM) to afford product 53-1 as a orange solid (190 mg, 44%).

Step 2:(2S)-1-{[(2S)-1-{[(3Z)-3-[(4-{[2-(Diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (53-2)

To a solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-{3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yloxycarbonyl}-ethoxycarbonyl)-ethylester (53-1) (3.0 g, 3.52 mmol) in dichloromethane (30 mL) was addedtrifluoroacetic acid (15 ml, 5V) at 0° C. After stirring at roomtemperature for 48 hours, the resulting reaction mixture was submergedin an ice bath and neutralized with trimethylamine. Excess solvents wereremoved in vacuo, the residue was diluted with dichloromethane andwashed with water. The crude product obtained upon evaporation ofvolatiles was purified by column chromatography to afford product 53-2as a reddish brown solid (0.7 g, 33%). ¹H-NMR (400 MHz, DMSO-d₆) δ 11.02(s, 1H), 7.78-7.69 (m, 2H), 7.66 (d, J=2 Hz, 1H), 6.90 (d, J=8 Hz, 1H),6.84 (dd, J=2 & 8 Hz, 1H), 5.52 (d, J=6 Hz, 1H), 5.40 (q, J=7 Hz, 1H),5.17 (q, J=7 Hz, 1H), 4.23 (quintet, 1H), 3.60-3.44 (m, 2H), 3.24-2.90(m, 6H), 2.47, (s, 3H), 2.44 (s, 3H), 1.64 (d, J=7 Hz, 3H), 1.48 (d, J=7Hz, 3H), 1.32 (d, J=7 Hz, 3H), 1.16 (t, 6H); MS m/z (M+H)⁺ 613.4.

To a solution of ethacrynic acid (54-1) (0.098 g, 0.32 mmol) indichloromethane (5 ml) was added N,N-diisopropylethylamine (0.1 ml, 0.65mmol), HATU (0.186 g, 0.48 mmol), (S)-2-hydroxy-propionic acid(S)-1-((S)-1-{3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yloxycarbonyl}-ethoxycarbonyl)-ethylester (53-2) (0.2 g, 0.32 mmol) and 4-dimethylaminopyridine (0.0039 g,0.032 mmol) at 0° C. After stirring for 12 hours at room temperature,the reaction mixture was quenched with water and extracted with ethylacetate. The organic layer were dried over sodium sulfate andconcentrated under reduced pressure. The residue was then purified bypreparative HPLC to afford product 54-2 as an orange solid (60 mg, 44%).¹H-NMR (400 MHz, DMSO-d₆) δ 13.69 (s, 1H), 10.99 (s, 1H), 7.71 (s, 1H),7.65 (d, J=2 Hz, 1H), 7.52 (t, 1H), 7.31 (d, J=9 Hz, 1H), 7.16 (d, J=9Hz, 1H), 6.89 (d, J=8 Hz, 1H), 6.83 (dd, J=2 & 8 Hz, 1H), 6.06 (s, 1H),5.55 (s, 1H), 5.40 (q, J=7 Hz, 1H), 5.32-5.10 (m, 4H), 3.36-3.30 (m,2H), 2.73-2.61 (m, 6H), 2.45 (s, 3H), 2.42 (s, 3H), 2.42-2.29 (m, 2H),1.63 (d, J=7 Hz, 3H), 1.52-1.46 (m, 6H), 1.09-1.097 (m, 9H); MS m/z(M+H)⁺ 897.7 and 899.7.

Example 6. Synthetic Examples of Dorzolmide-Sunitinib Bis-Prodrugs

Step 1:4-{[(2S)-1-{[(2S)-1-(Benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-4-oxobutanoicacid (55-1)

To a solution of succinic acid (0.93 g, 3.96 mmol) in dichloromethane(10 mL) was added EDCI.HCl (2.27 g, 11.9 mmol), hydroxybenzotriazole(0.109 g, 0.79 mmol), (S)-2-hydroxy-propionic acid(S)-1-benzyloxycarbonyl-ethyl ester (1-2) (1.0 g, 3.96 mmol) and4-dimethylaminopyridine (48 mg, 0.39 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 1 hour, and the resulting reactionmixture was quenched with water (100 mL), extracted with dichloromethane(150×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (230-400) column chromatography (3% methanol indichloromethane) to afford a pale yellow liquid (1.0 g, 71%). ¹H NMR(400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 7.44-7.30 (m, 5H), 5.19 (m, 3H),5.05 (q, J=7.2 Hz, 1H), 2.62-2.48 (m, 4H), 1.5 (d, J=6.8 Hz, 3H), 1.4(d, J=6.8 Hz, 3H); MS m/z (M−H) 251.0.

Step 2: Succinic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (55-2)

To a solution of4-{[(2S)-1-{[(2S)-1-(benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-4-oxobutanoicacid (55-1) (0.26 g, 0.756 mmol) in dimethylformamide (2 mL) was addedN,N-diisopropylethylamine (0.19 mL, 1.05 mmol), HATU (0.306 g, 0.807mmol), and hydroxy sunitinib (48-3) (0.2 g, 0.504 mmol) at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 2 hours and theresulting reaction mixture was quenched with water (50 mL), extractedwith dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel columnchromatography (5% methanol in DCM) to afford an orange solid (200 mg,55%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.73 (s, 1H), 10.98 (s, 1H), 9.12 (s,1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.43-7.29 (m, 6H),6.91-6.80 (m, 2H), 5.23-5.06 (m, 4H), 3.70-3.56 (m, 3H), 3.22-3.30 (m,6H), 2.85 (dd, J=15.5, 8.9 Hz, 2H), 2.45 (d, J=14.7 Hz, 2H), 2.4-2.61(m, 6H), 1.46 (d, J=6.8 Hz, 3H), 1.39 (d, J=7.2 Hz, 3H), 1.15 (m, 6H);MS m/z (M+H) 731.7.

Step 3:(2S)-2-{[(2S)-2-[(4-{[(3Z)-3-[(4-{[2-(Diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl]oxy}-4-oxobutanoyl)oxy]propanoyl]oxy}propanoicacid (55-3)

To a 100 mL autoclave vessel was added a solution of succinic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (55-2) (0.2 g, 0.27 mmol) in methanol (10 mL) and 10% Pd/C (40 mg,50% wet) at 25-30° C. The reaction mixture was stirred at roomtemperature under hydrogen pressure (1 kg/cm²) for 30 minutes. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite. Then volatiles were evaporated under reduced pressure to afforda reddish orange solid (160 mg, 91%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.72(s, 1H), 10.98 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.61 (d, J=2.1 Hz,1H), 6.91-6.80 (m, 2H), 5.11 (q, J=7.0 Hz, 1H), 4.99 (q, J=7.0 Hz, 1H),3.54-3.65 (m, 3H), 3.1-3.32 (m, 6H), 2.91-2.74 (m, 2H), 2.45 (d, J=14.7Hz, 2H), 2.5-2.7 (m, 6H), 1.50-1.38 (m, 6H), 1.36-1.15 (m, 6H); MS m/z(M+H) 641.6.

Step 4:(3Z)-3-[(4-{[2-(Diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl1-(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-ylbutanedioate (55-4)

To a solution of dorzolamide (19-1) (0.8 g, 2.22 mmol) indichloromethane (10 mL) was added N,N-diisopropylethylamine (0.05 mL,0.311 mmol) at 0° C. After 30 minutes, succinic acid(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethyl ester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (55-3) (0.18 g, 0.25 mmol), EDCI.HCl (59 mg, 0.311 mmol),hydroxybenzotriazole (5 mg, 0.038 mmol), and 4-dimethylaminopyridine(0.1 mg, 0.138 mmol) were added at 0° C. The reaction mixture wasallowed to stir at 25-30° C. for 2 hours and the resulting reactionmixture was quenched with water (100 mL), extracted with dichloromethane(200×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel column chromatography (5% methanol in DCM) toafford an orange solid (50 mg, 38%). ¹H-NMR (400 MHz, DMSO-d₆) δ 13.71(s, 1H), 10.96 (s, 1H), 7.70-7.65 (m, 2H), 7.61 (s, Hz, 1H), 7.5-7.3 (m,1H), 6.90-6.81 (m, 2H), 5.03 (q, 1H), 4.79 (q, 1H), 3.93-3.82 (m, 2H),3.6-3.5 (m, 2H), 2.9-3.3 (m, 6H), 2.87-2.81 (m, 2H), 2.79-2.72 (m, 2H),2.46 (s, 3H), 2.43 (s, 3H), 1.48 (d, 3H), 1.36-1.00 (m, 12H), 0.88-0.86(m, 3H). MS m/z (M+H)⁺ 947.7.

Step 1:(2S)-1-{[(2S)-1-(Benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (56-1)

To a solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethyl ester (2-2) (6.5 g,11.55 mmol) in tetrahydrofuran (65 mL) was added tetra-n-butylammoniumfluoride (17.32 mL, 17.32 mmol) and acetic acid (1.03 mL, 17.32 mmol) at0° C. The reaction mixture was allowed to stir at room temperature for 1hour and the resulting reaction mixture was concentrated under reducedpressure. Crude product obtained upon evaporation of the volatiles waspurified through silica gel column chromatography (20% ethyl acetate inhexane) to afford a colorless liquid (2.5 g, 67%).

Step 2:4-{[(2S)-1-{[(2S)-1-{[(2S)-1-(Benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-4-oxobutanoicacid (56-2)

To a solution of succinic acid (1.8 g, 15.4 mmol) in dichloromethane (20mL) was added N,N-diisopropylethylamine (4.2 mL, 23.14 mmol), EDCI.HCl(4.4 g, 23.14 mmol), hydroxybenzotriazole (212 mg, 1.54 mmol),(2S)-1-{[(2S)-1-(benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (56-1) (2.5 g, 7.7 mmol), and4-dimethylaminopyridine (93 mg, 0.77 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 1 hour and the resulting reactionmixture was quenched with water (100 mL), extracted with dichloromethane(150×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel (230-400) column chromatography (2% methanol inDCM) to afford a colorless liquid (2.1 g, 65%).

Step 3:1-(2S)-1-{[(2S)-1-{[(2S)-1-(Benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylbutanedioate (56-3)

To a solution of4-{[(2S)-1-{[(2S)-1-{[(2S)-1-(benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-4-oxobutanoicacid (56-2) (2.0 g, 4.53 mmol) in dimethylformamide (5 mL) were addedN,N-diisopropylethylamine (1.1 mL, 6.05 mmol), HATU (1.8 g, 4.83 mmol)and 5-hydroxyl Sunitinib (48-3) (1.2 g, 3.02 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. for 5 hours and the resultingreaction mixture was quenched with water (30 mL), extracted withdichloromethane (50×3 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (230-400) column chromatography (4%methanol in DCM) to afford a reddish brown solid (1.6 g, 66%).

Step 4:(2S)-2-{[(2S)-2-{[(2S)-2-[(4-{[(3Z)-3-[(4-{[2-(Diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl]oxy}-4-oxobutanoyl)oxy]propanoyl]oxy}propanoyl]oxy}propanoicacid (56-4)

To a 100 mL autoclave vessel was added a solution of1-(2S)-1-{[(2S)-1-{[(2S)-1-(benzyloxy)-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylbutanedioate (56-3) (1.5 g, 1.87 mmol) in methanol (30 mL) and 10% Pd/C(220 mg, 50% wet) at 25-30° C. The reaction mixture was stirred at roomtemperature under hydrogen pressure (1 kg/cm²) for 30 minutes. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite. Then volatiles were evaporated under reduced pressure to afforda reddish orange solid 1.0 g (76%).

Step 5:(3Z)-3-[(4-{[2-(Diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl1-(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-ylbutanedioate (56-5)

To a solution of dorzolamide (0.2 g, 0.555 mmol) in dichloromethane (5mL) was added N,N-diisopropylethylamine (0.16 mL, 0.889 mmol) at 0° C.After 30 minutes, succinic acid(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethyl ester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (0.514 g, 0.722 mmol), EDCI.HCl (0.169 g, 0.889 mmol),hydroxybenzotriazole (15 mg, 0.111 mmol), and 4-dimethylaminopyridine (7mg, 0.055 mmol) were added at 0° C. The reaction mixture was allowed tostir at 25-30° C. for 2 hours and the resulting reaction mixture wasquenched with water (50 mL), extracted with dichloromethane (50×3 mL),dried over sodium sulfate, and concentrated under reduced pressure. Thecrude product obtained upon evaporation of volatiles was purified bysilica gel column chromatography (5% methanol in DCM) to afford anorange solid (80 mg, 31%). ¹H-NMR (400 MHz, DMSO-d₆) δ 13.72 (s, 1H),10.96 (s, 1H), 7.72-7.66 (m, 2H), 7.60 (d, J=2 Hz, 1H), 7.43 (s, 1H),6.91-6.82 (m, 2H), 5.16-5.07 (m, 2H), 4.79 (q, J=7 Hz, 1H), 4.05-3.84(m, 2H), 3.55-3.45 (m, 2H), 3.05-2.94 (m, 6H), 2.88-2.82 (m, 2H),2.80-2.72 (m, 2H), 2.70-2.55 (m, 2H), 2.46, (s, 3H), 2.43 (s, 3H),2.42-2.25 (m, 2H), 1.50-1.42 (m, 6H), 1.34-1.23 (m, 6H), 1.15 (t, 6H),1.04 (t, 3H). MS(+) m/z (M+H)⁺ 1019.5. MS(−) m/z (M−H)⁻ 1017.8.

Step 1:N-{3-[1-[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-succinamicacid(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (57-1)

To a solution of succinic acidmono-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethyl}ester (56-2) (2.4 g, 5.68 mmol) in dimethylformamide (5 mL) was addedN,N-diisopropylethylamine (1.3 mL, 7.58 mmol), HATU (2.3 g, 6.06 mmol),and 5-amino Sunitinib (47-1) (1.5 g, 3.79 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. for 30 minutes and theresulting reaction mixture was quenched with water (30 mL), extractedwith dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified through silica gel (230-400)column chromatography (2% methanol in DCM) to afford a reddish brownsolid (2.1 g, 69%).

Step 2:N-{3-[1-[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-succinamicacid (S)-1[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (57-2)

To a 100 mL autoclave vessel was added a solution ofN-{3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-succinamicacid(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (57-1) (1.5 g, 1.87 mmol) in methanol (30 mL) and 10% Pd/C (220mg, 50% wet) at 25-30° C. The reaction mixture was stirred at roomtemperature under hydrogen pressure (1 kg/cm²) for 30 minutes. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite. Then volatiles were evaporated under reduced pressure to afforda reddish orange solid (0.9 g, 69%).

Step 3:(2S)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(Ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl3-{[(3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl]carbamoyl}propanoate(57-3)

To a solution of dorzolamide (19-1) (0.15 g, 0.416 mmol) indichloromethane (5 mL) was added N,N-diisopropylethylamine (0.12 mL,0.666 mmol) at 0° C. After 30 minutes, N-{3-[1-[4-(2-diethyl amino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-succinamicacid (S)-1 [(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (57-2) (0.385 g, 0.541 mmol), EDCI.HCl (0.127 g, 0.666 mmol),hydroxybenzotriazole (11 mg, 0.0833 mmol), and 4-dimethylaminopyridine(5 mg, 0.0416 mmol) were added at 0° C. The reaction mixture was allowedto stir at 25-30° C. for 2 hours and the resulting reaction mixture wasquenched with water (50 mL), extracted with dichloromethane (50×3 mL),dried over sodium sulfate, and concentrated under reduced pressure. Thecrude product obtained upon evaporation of volatiles was purifiedthrough silica gel column chromatography (5% methanol in DCM) to affordan orange solid (110 mg, 25%). ¹H-NMR (400 MHz, DMSO-d₆) δ 13.70 (s,1H), 10.85 (s, 1H), 9.87 (s, 1H), 7.93 (bs, 1H), 7.65 (t, 1H), 7.46 (s,1H), 7.41 (bs, 1H), 7.21-7.15 (m, 1H), 6.81 (d, 1H), 5.13-5.04 (m, 2H),4.79 (q, J=7 Hz, 1H), 3.98-3.82 (m, 2H), 3.5-3.4 (m, 2H), 3.05-2.85 (m,6H), 2.75-2.55 (m, 6H), 2.45, (s, 3H), 2.41 (s, 3H), 2.40-2.23 (m, 2H),1.50-1.40 (m, 6H), 1.35-1.24 (m, 6H), 1.13 (t, 6H), 1.04 (t, 3H). MS(+)m/z (M+H)⁺ 1018.7 and (M+2H)⁺⁺ 510.0.

Step 1: (S)-2-Hydroxy-propionic acid(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (58-1)

To a solution of (S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (3-1) (11.0 g, 0.0173 mol) in tetrahydrofuran (110 mL) was addedtetra-n-butylammonium fluoride (25.6 mL, 1.0 M, 0.0259 mol) and aceticacid (1.5 mL, 0.0259 mol) at 0° C. The reaction mixture was allowed tostir at room temperature for 1 hour and the resulting reaction mixturewas concentrated under reduced pressure. Crude product obtained uponevaporation of the volatiles was purified by silica gel columnchromatography (20% Ethyl acetate in hexane) to give product ascolorless liquid (5.5 g, 80%). 1H NMR (400 MHz, DMSO-d₆) δ 7.44-7.30 (m,5H), 5.49 (d, J=5.9 Hz, 1H), 5.23-5.07 (m, 5H), 4.26-4.15 (m, 1H), 1.43(dd, J=13.1, 7.0 Hz, 9H), 1.28 (d, J=6.8 Hz, 3H); MS m/z (M+NH₄ ⁺) 414.0

Step 2: Succinic acidmono-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethyl)ester (58-2)

To a solution of succinic acid (1.7 g, 15.1 mmol) in dichloromethane (10mL) was added N,N-diisopropylethylamine (4 mL, 22.7 mmol), EDCI.HCl(4.33 g, 22.7 mmol), hydroxybenzotriazole (208 mg, 1.51 mmol),(S)-2-hydroxy-propionic acid(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethylester (58-1) (3 g, 7.5 mmol), and 4-dimethylaminopyridine (92 mg, 0.75mmol) at 0° C. The reaction mixture was allowed to stir at 25-30° C. for1 hour and the resulting reaction mixture was quenched with water (100mL), extracted with dichloromethane (150×3 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The crude productobtained upon evaporation of volatiles was purified by silica gel(230-400) column chromatography (2% methanol in DCM) to afford acolorless liquid (2.5 g, 66%). 1H NMR (400 MHz, DMSO-d₆) δ 12.25 (s,1H), 7.43-7.30 (m, 5H), 5.24-5.16 (m, 5H), 5.17 (q, J=7.2, 1H),2.67-2.47 (m, 4H), 1.50-1.33 (m, 12H); MS m/z (M+NH₄ ⁺) 514.6

Step 3: Succinic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (58-3)

To a solution of succinic acidmono-((S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethyl)ester (1.8 g, 3.7 mmol) in dimethylformamide (5 mL) was addedN,N-diisopropylethylamine (0.19 mL, 1.05 mmol), HATU (1.5 g, 4.0 mmol),and 5-hydroxyl Sunitinib (1.0 g, 2.5 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 2 hours and the resulting reactionmixture was quenched with water (50 mL), extracted with dichloromethane(50×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude product obtained upon evaporation of volatiles waspurified by silica gel column chromatography (5% methanol in DCM) toafford a reddish brown solid (1.5 g, 68%). 1H NMR (400 MHz, DMSO-d₆) δ9.08 (s, 1H), 7.76-7.73 (m, 1H), 7.69 (s, 1H), 7.61 (d, J=2.1 Hz, 1H),7.43-7.29 (m, 6H), 6.92-6.80 (m, 2H), 5.25-5.08 (m, 6H), 3.56 (m, 3H),3.23 (m, 6H), 2.91-2.82 (m, 2H), 2.81-2.70 (m, 2H), 2.45 (d, J=14.4 Hz,6H), 1.50-1.37 (m, 12H), 1.26-1.21 (m, 6H); MS m/z (M+H) 875.7.

Step 4: Succinic acid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (58-4)

To a 100 mL autoclave vessel was added a solution of succinic acid(S)-1-{(S)-1-[(S)-1-((S)-1-benzyloxycarbonyl-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (58-3) (1 g, 1.14 mmol) in methanol (20 mL) and 10% Pd/C (150 mg,50% wet) at 25-30° C. The reaction mixture was stirred at roomtemperature under hydrogen pressure (1 kg/cm²) for 30 minutes. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite. Then volatiles were evaporated under reduced pressure to afforda reddish orange solid (0.8 g, 89%). 1H NMR (400 MHz, DMSO-d₆) δ 13.8(s, 1H), 10.97 (s, 1H), 7.8 (m, 1H), 7.70 (s, 1H), 7.60 (s, 1H),6.80-6.90 (m, 2H), 5.25-5.09 (m, 4H), 4.92 (q, J=6.8 Hz, 1H), 3.54 (d,J=6.3 Hz, 2H), 3.1-3.3 (m, 6H), 2.98-2.6 4H), 2.3-2.5 (m, 6H), 1.48-1.30(m, 12H), 1.25-1.19 (6H); MS m/z (M+H) 785.9.

Step 5:(3Z)-3-[(4-{[2-(Diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl1-(2S)-1-{[(2)-1-{[(2S)-1-[(1S)-1-({[(2S,4S)-4-(ethylamino)-2-methyl-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[2,3-b]thiopyran-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-ylbutanedioate (58-5)

To a solution of dorzolamide (19-1) (0.3 g, 0.83 mmol) indichloromethane (5 mL) was added N,N-diisopropylethylamine (0.25 mL,1.33 mmol) at 0° C. After 30 minutes, succinic acid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (58-4) (0.85 g, 1.08 mmol), EDCI.HCl (0.25 g, 1.33 mmol),hydroxybenzotriazole (23 mg, 0.166 mmol), and 4-dimethylaminopyridine(10 mg, 0.08 mmol) were added at 0° C. The reaction mixture was allowedto stir at 25-30° C. for 2 hours and the resulting reaction mixture wasquenched with water (100 mL), extracted with dichloromethane (200×3 mL),dried over sodium sulfate, and concentrated under reduced pressure. Thecrude product obtained upon evaporation of volatiles was purified bysilica gel column chromatography (5% methanol in DCM) to afford anorange solid (350 mg, 38%). ¹H-NMR (400 MHz, DMSO-d₆) δ 13.72 (s, 1H),10.96 (s, 1H), 7.74-7.67 (m, 2H), 7.60 (d, J=2 Hz, 1H), 7.52-7.41 (m,1H), 6.90-6.82 (m, 2H), 5.21-5.04 (m, 3H), 4.79 (q, J=7 Hz, 1H), 4.2-3.8(m, 2H), 3.57-3.44 (m, 2H), 3.25-2.95 (m, 6H), 2.87-2.81 (m, 2H),2.80-2.72 (m, 2H), 2.70-2.55 (m, 2H), 2.46, (s, 3H), 2.43 (s, 3H),2.42-2.24 (m, 2H), 1.50-1.42 (m, 9H), 1.34 (d, 3H), 1.29 (d, 3H), 1.18(t, 6H), 1.06 (t, 3H). MS(+) m/z (M+H)⁺ 1091.6.

Example 7. Synthetic Examples of Brinzolmide-Sunitinib Bis-Prodrugs

To a solution of brinzolamide (32-1) (0.2 g, 0.52 mmol) and succinicacid (S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethylester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (56-4) (0.48 g, 0.677 mmol) in dichloromethane (10 mL) was addedEDCI.HCl (0.149 g, 0.783 mmol), hydroxybenzotriazole (14 mg, 0.104mmol), and 4-dimethylaminopyridine (6 mg, 0.052 mmol) at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 2 hours and theresulting reaction mixture was quenched with water (50 mL), extractedwith dichloromethane (50×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel columnchromatography (6% methanol in DCM) to afford an orange solid (150 mg,26%). ¹H-NMR (400 MHz, DMSO-d₆) δ 13.72 (s, 1H), 10.96 (s, 1H), 7.71(bs, 1H), 7.68 (s, 1H), 7.60 (d, J=2 Hz, 1H), 7.51 (t, 1H), 6.90-6.82(m, 2H), 5.15-5.04 (m, 2H), 4.79 (q, J=7 Hz, 1H), 4.15-4.00 (m, 1H),3.85-3.70 (m, 2H), 3.60-3.45 (m, 2H), 3.45-3.35 (m, 2H), 3.22 (s, 3H),3.22-3.05 (m, 6H), 2.86-2.80 (m, 2H), 2.80-2.73 (m, 2H), 2.70-2.55 (m,2H), 2.47 (s, 3H), 2.44 (s, 3H), 1.77 (quintet, 2H), 1.50-1.42 (m, 6H),1.28 (d, 3H), 1.20 (t, 6H), 1.03 (t, 3H). MS(+) m/z (M+H)⁺ 1078.6 and(M+2H)⁺⁺539.9.

To a solution of brinzolamide (32-1) (0.2 g, 0.52 mmol) and succinicacid(S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethoxycarbonyl}-ethylester3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylester (58-4) (0.56 g, 0.71 mmol) in dichloromethane (10 mL) was addedEDCI.HCl (0.149 g, 0.78 mmol), hydroxybenzotriazole (14 mg, 0.10 mmol),and 4-dimethylaminopyridine (6 mg, 0.052 mmol) at 0° C. The reactionmixture was allowed to stir at 25-30° C. for 2 hours and the resultingreaction mixture was quenched with water (50 mL), extracted withdichloromethane (50×3 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The crude product obtained upon evaporation ofvolatiles was purified by silica gel (230-400) column chromotography (6%methanol in DCM) to afford an orange solid (280 mg, 46%). ¹H-NMR (400MHz, DMSO-d₆) δ 13.73 (s, 1H), 10.97 (s, 1H), 7.72 (bs, 1H), 7.68 (s,1H), 7.60 (d, J=2 Hz, 1H), 7.50 (bs, 1H), 6.89-6.81 (m, 2H), 5.19-5.03(m, 3H), 4.79 (q, J=7 Hz, 1H), 4.15-4.00 (m, 1H), 3.8-3.7 (m, 2H),3.56-3.45 (m, 2H), 3.45-3.35 (m, 2H), 3.22 (s, 3H), 3.22-3.06 (m, 6H),2.86-2.80 (m, 2H), 2.80-2.72 (m, 2H), 2.70-2.55 (m, 2H), 2.47 (s, 3H),2.43 (s, 3H), 1.79 (quintet, 2H), 1.50-1.43 (m, 9H), 1.28 (d, 3H), 1.19(t, 6H), 1.02 (t, 3H). MS(+) m/z (M+H)⁺ 1151.2.

Step 1: Hexanedioic acidmono-{3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}ester (61-1)

To a solution of hexanedioic acid (0.368 g, 2.52 mmol) indichloromethane (20 mL) was added N,N-diisopropylethylamine (0.69 mL,3.78 mmol), HATU (1.15 g, 3.02 mmol), 5-hydroxy Sunitinib (48-3) (0.1 g,2.52 mol), and 4-dimethylaminopyridine (30 mg, 0.25 mmol) at 0° C. Thereaction mixture was allowed to stir at 25-30° C. for 1 hour and theresulting reaction mixture was quenched with water (100 mL), extractedwith dichloromethane (150×3 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product obtained uponevaporation of volatiles was purified by silica gel (230-400) columnchromatography (8% methanol in dichloromethane) to afford an orangesolid (500 mg, 37%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.67 (s, 1H), 12.03(s, 1H), 10.93 (s, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.49 (t, J=5.6 Hz,1H), 6.90-6.82 (m, 2H), 2.67-2.53 (m, 4H), 2.43 (m, 6H), 1.63 (m, 4H),1.02 (t, J=7.1 Hz, 6H); MS m/z (M+H) 525.3.

Step 2:(3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl5-{ethyl[(4R)-6-{[(2S)-2-{[(2S)-2-{[(2S)-2-hydroxypropanoyl]oxy}propanoyl]oxy}propanamido]sulfonyl}-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-4-yl]carbamoyl}pentanoate(61-2) and(3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl1-(2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-ylhexanedioate (61-3)

To a solution of hexanedioic acidmono-{3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}ester (61-1) (0.272 g, 0.52 mmol) in dimethylformamide (5 mL) was addedN,N-diisopropylethylamine (0.15 mL, 0.80 mmol), HATU (0.228 g, 0.60mmol),(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl(2S)-2-hydroxypropanoate (34-2) (0.24 g, 0.40 mmol) and4-dimethylaminopyridine (30 mg, 0.25 mmol) at 0° C. The reaction mixturewas allowed to stir at 25-30° C. for 1 hour and the resulting reactionmixture was quenched with water (100 mL), extracted with dichloromethane(150×3 mL), dried over sodium sulfate, and concentrated under reducedpressure. The crude mixture obtained upon evaporation of volatiles waspurified by silica gel column chromatography (10% methanol indichloromethane) to afford compounds 61-2 (35 mg) and 61-3 (35 mg)(18%).

61-2: ¹H-NMR (400 MHz, DMSO-d₆) δ 13.67 (s, 1H), 10.9 (bs, 1H), 7.68 (s,2H), 7.64 (bs, 1H), 7.42 (t, 1H), 7.06 (s, 1H), 6.9-6.8 (m, 2H), 5.4(bs, 1H), 5.01 (q, 1H), 4.77 (q, 1H), 4.19 (quintet, 1H), 3.84-3.65 (m,2H), 3.5-3.25 (m, nH), 2.6-2.4 (m, 12H), 1.82 (quintet, 2H), 1.75-1.60(m, 4H), 1.46 (d, 3H), 1.27 (d, 3H), 1.20-1.05 (m, 2H), 1.00-0.92 (m,9H). MS(+) m/z (M+H)⁺ 1106.8.

61-3: ¹H-NMR (400 MHz, DMSO-d₆) δ 13.73 (s, 1H), 10.95 (s, 1H), 9.3-8.9(bs, 1H), 7.80-7.68 (m, 2H), 7.63 (d, J=2 Hz, 1H), 7.50 (bs, 1H),6.89-6.82 (m, 2H), 5.11-5.02 (m, 2H), 4.79 (q, J=7 Hz, 1H), 4.15-3.95(m, 1H), 3.84-3.65 (m, 2H), 3.64-3.55 (m, 2H), 3.4-3.1 (m, 12H), 2.7-2.5(m, 4H), 2.47 (s, 3H), 2.41 (s, 3H), 1.81 (quintet, 2H), 1.75-1.60 (m,4H), 1.48 (d, 3H), 1.44 (d, 3H), 1.29 (d, 3H), 1.21 (t, 6H), 1.00 (t,3H). MS(+) m/z (M+H)⁺ 1106.7.

Example 8. General Routes of Synthesis to Compounds of Formula I andFormula II

Scheme 62:

A compound of the present invention can be prepared, for example, from aprostaglandin. In Step 1 the prostaglandin's (62-1) hydroxyl groups areacylated as known in the art to afford a protected species (62-2). InStep 2 the protected species (62-2) is converted to an activatedelectrophile (62-3) as known in the art to subsequently be reacted withan appropriately substituted alcohol in Step 3 to afford an ester (62-4)which in a typical embodiment is hydrophobic to afford a compound ofFormula I. In Step 1, if a hydroxyl group is present on L² it isacylated.

Scheme 63:

A compound of the present invention can be prepared with variousdifferent substituents, for example, from a prostaglandin. In Step 1 theprostaglandin's (62-1) hydroxyl groups are orthogonally protected asknown in the art to afford a protected species (63-1). In Step 2 theprotected species (63-1) is converted to an activated electrophile(63-2) as known in the art to subsequently be reacted with anappropriately substituted alcohol in Step 3 to afford an ester (63-3).In Step 4 the prostaglandin is selectively deprotected to afford aselectively protected species (63-4 or 63-7). In Step 5 theprostaglandin (63-4 or 63-7) is subjected to an appropriatelysubstituted acyl chloride to afford an ester (63-5 or 63-8). In Step 6the prostaglandin (63-5 or 63-8) is further deprotected to afford acompound of either Formula I (63-6) or Formula II (63-7) depending onthe choice of acyl chloride and alcohol functionality.

Example 9. Representative Routes of Synthesis to Compounds of Formula Iand Formula II

Scheme 64:

A compound of the present invention can be prepared, for example, from aprostaglandin. In Step 1 the prostaglandin's (64-1) hydroxyl groups areprotected as known in the art with a silyl chloride to afford aprotected species (64-2). In Step 2 the appropriately substitutedcarboxylic acid (64-2) is subjected to thionyl chloride as known in theart to afford an acyl chloride (64-3). In Step 3 the appropriatelysubstituted acyl chloride (64-3) is subjected to an alcohol to afford anester (64-4) which in a typical embodiment is hydrophobic. In Step 4 theappropriately substituted silyl ethers (64-5) are deprotected to afforda hydroxyl species (64-5). In Step 5 the appropriately substitutedalcohol (65-5) is acylated as known in the art to afford a compound(64-6) of Formula I.

Scheme 65:

A compound of the present invention can be prepared, for example, from aprostaglandin. In Step 1 the prostaglandin's (65-1) hydroxyl groups areprotected as known in the art with a silyl chloride to afford aprotected species (65-2). In Step 2 the appropriately substitutedcarboxylic acid (65-2) is subjected to thionyl chloride as known in theart to afford an acyl chloride (65-3). In Step 3 the appropriatelysubstituted acyl chloride (65-3) is subjected to an alcohol to afford anester (65-4). In Step 4 the less hindered silyl ether (65-4) isdeprotected as disclosed by Roush to afford a partially protectedprostaglandin (65-5). In Step 5 the appropriately substituted alcohol(65-5) is subjected to an acyl chloride to afford an ester (65-6), whichin a typical embodiment is hydrophobic. In Step 6 the remaining silylether(s) (65-6) are deprotected as known in the art to afford a compound(65-7) of Formula 1.

Scheme 66:

A compound of the present invention can be prepared, for example, from aprostaglandin. In Step 1 the prostaglandin's (65-1) hydroxyl groups areprotected as known in the art with a silyl chloride to afford aprotected species (65-2). In Step 2 the appropriately substitutedcarboxylic acid (65-2) is subjected to thionyl chloride as known in theart to afford an acyl chloride (65-3). In Step 3 the appropriatelysubstituted acyl chloride (65-3) is subjected to an alcohol to afford anester (65-4). In Step 4 the less hindered silyl ether is deprotected asdisclosed by Roush to afford a partially protected prostaglandin (65-5).In Step 5 the appropriately substituted alcohol is subjected to a bulkysilyl chloride to afford an orthogonally protected species (66-1). InStep 6 the least bulky silyl ether is deprotected as disclosed byBoschelli to afford a partially protected prostaglandin (66-2). In Step7 the appropriately substituted alcohol is subjected to an acyl chlorideto afford an ester (66-3 or 66-5), which in a typical embodiment ishydrophobic. In Step 8 the remaining silyl ether(s) are deprotected asknown in the art to afford a compound of Formula I (66-4) or Formula II(66-6).

Example 10. General Routes of Synthesis to Compounds of Formula III,Formula IV, Formula V, and Formula VI

Scheme 67:

A compound of the present invention can be prepared, for example, fromprecursors to various carbonic anhydrase inhibitors (CAIs). In Step 1the CAI precursor (67-1, 67-4, 67-7) is protected as known in the art toafford a protected species (67-2, 67-5, 67-8). In Step 2 the protectedspecies is halogenated as known the art to allow furtherfunctionalization en route to compounds of Formula III (67-6), FormulaIV (67-3), Formula V (67-8), and Formula VI (67-8).

Scheme 68:

A compound of the present invention can be prepared, for example, fromprecursors to various carbonic anhydrase inhibitors (CAIs). In Step 1the CAI precursor (67-3) is directly converted to a disulfide species(68-1). Alternatively, in Step 2 the protected species is firstconverted to a sulfide (68-2) and then in Step 3 oxidized to a disulfidespecies (68-1) to allow further functionalization en route to compoundsof Formula III, Formula IV, Formula V, or Formula VI.

Scheme 69:

A compound of the present invention can be prepared, for example, fromprecursors to various carbonic anhydrase inhibitors (CAIs). In Step 1the CAI precursor (68-1) is directly converted to a sulfinyl species(69-1). In Step 2 the sulfinyl species is converted to either analdimine or a ketamine (69-2) which in a typical embodiment ishydrophobic. In Step 3 the sulfinyl aldimine or ketimine is converted toa sulfonyl aldimine or ketamine (69-3). In Step 4 the sulfonyl aldimineor ketimine is deprotected to afford a compound (69-4) of Formula III,Formula IV, Formula V, or Formula VI.

Scheme 70:

A compound of the present invention can be prepared, for example, fromvarious carbonic anhydrase inhibitors (CAIs). In Step 1 the CAIprecursor (70-1) is protected as known in the art to afford a protectedspecies (70-2). In Step 2 the sulfonyl species is converted to either analdimine or a ketimine (69-3) which in a typical embodiment ishydrophobic. In Step 3 the sulfonyl aldimine or ketimine is deprotectedas known in the art to afford a compound (69-4) of Formula III, FormulaIV, Formula V, or Formula VI.

Example 11. Representative Routes of Synthesis to Compounds of FormulaIII, Formula IV, Formula V, and Formula VI

Scheme 71:

A compound of the present invention can be prepared, for example, fromprecursors to various carbonic anhydrase inhibitors (CAIs). In Step 1the appropriately substituted CAI precursor (67-1, 67-4, 67-7) isprotected as known in the art to afford a carbamate protected species(71-1, 71-3). In Step 2 the appropriately substituted CAI precursor issubjected to bromine as known in the art to afford an aryl bromide(71-2, 71-4, 71-5).

Scheme 72:

A compound of the present invention can be prepared, for example, fromprecursors to various carbonic anhydrase inhibitors (CAIs). In Step 1the appropriately substituted CAI precursor (71-2) is directly convertedto a disulfide species (72-1) using a method disclosed by Soleiman andcoworkers. Alternatively, in Step 2 the protected species (71-2) isfirst converted to a sulfide (72-2) and then in Step 3 oxidized to adisulfide species (72-1) using a method disclosed by Gholami to allowfurther functionalization en route to compounds of Formula III, FormulaIV, Formula V, and Formula VI.

Scheme 73:

A compound of the present invention can be prepared, for example, fromprecursors to various carbonic anhydrase inhibitors (CAIs). In Step 1the appropriately substituted CAI precursor (72-1) is subjected to analcohol and N-bromosuccinimide to afford a sulfinyl species (73-1). InStep 2 the appropriately substituted sulfinyl species is converted to asulfonamide (73-2) as known in the art. In Step 3 the appropriatelysubstituted sulfonamide (73-2, 73-8, 73-11, 73-14) is subjected to analdehyde or ketone to afford an aldimine (73-3A, 73-3B, 73-9) orketamine (73-12, 73-15, 73-17) respectively, which in a typicalembodiment is hydrophobic. In Step 4 the sulfonyl aldimine or ketimineis deprotected as known in the art to afford a compound of Formula III(73-13), Formula IV (73-4A and 73-4B), Formula V, or Formula VI. In Step5 an appropriately substituted unsaturated fatty ester (73-5) isprotected as known in the art to afford a poly-chloro ester (73-6). InStep 6 the appropriately substituted ester is reduced with LAH as knownin the art to afford an aldehyde (67-7). In Step 7 an appropriatelysubstituted sulfonyl aldimine (73-9) can be deprotected as known in theart to afford an unsaturated sulfonyl aldimine (73-10) of Formula III,Formula IV, Formula V, or Formula VI.

Scheme 74:

A compound of the present invention can be prepared, for example, fromvarious carbonic anhydrase inhibitors (CAIs). In Step 1 theappropriately substituted CAI precursor (74-1, 74-5) is protected asknown in the art to afford a carbamate species (74-2, 74-6, 74-16). InStep 2 the sulfonyl species is subjected to an aldehyde as known in theart to afford an aldimine precursor (74-3, 74-7, 74-10, 74-12, 74-14,74-16), which in a typical embodiment is hydrophobic. In Step 3 thede-sulfination affords an aldimine that is a protected compound (74-4,74-8, 74-11, 74-13, 74-15, 74-17) of Formula III, Formula IV, Formula V,or Formula VI.

Example 12. General Routes of Synthesis to Compounds of Formula VII

Scheme 75:

A compound of the present invention can be prepared, for example, from aprostaglandin and a carbonic anhydrase inhibitor. In Step 1 theprostaglandin's (62-1) hydroxyl groups are protected as known in the artto afford a protected species (63-1). In Step 2 the protected species(63-1) is converted to an activated electrophile (63-2) as known in theart to subsequently be reacted with an appropriately substitutednucleophile in Step 3 to afford an ester or amide with attachment eitherdirectly or indirectly through a linker to a carbonic anhydraseinhibitor (75-1). In Step 4 the prostaglandin covalently bound to acarbonic anhydrase inhibitor is deprotected to afford a compound ofFormula VII (75-2).

Example 13. Representative Routes of Synthesis to Compounds of FormulaVII

Scheme 76:

A compound of the present invention can be prepared, for example, from aprostaglandin and a carbonic anhydrase inhibitor. In Step 1 theappropriately substituted prostaglandin (76-1, 76-3) is subjected to asilyl chloride to afford a fully protected silyl ether species (76-2,76-4). In Step 2 the appropriately substituted prostaglandin issubjected to thionyl chloride as known in the art to afford an acylchloride (76-3, 76-5, 76-7). In Step 3 the appropriately substitutedacyl chloride is subjected to either an amine (76-6) or alcohol (76-4)to afford an amide or ester respectively which can be used in Scheme 77to afford a compound of Formula VII.

Scheme 77:

A compound of the present invention can be prepared, for example, from aprostaglandin and a carbonic anhydrase inhibitor. In Step 1 thepreviously prepared acyl chloride (76-5, 77-3, 76-7, 77-8) is subjectedto a carbonic anhydrase inhibitor (CAI) (74-1) to afford a prostaglandincoupled to a CAI species (77-1, 77-4, 77-6, 77-9). In Step 2 theappropriately substituted coupled species is deprotected as known in theart to afford a compound (77-2, 77-5, 77-7, 77-10) of Formula VII.

Scheme 78:

A compound of the present invention can be prepared, for example, from aprostaglandin and a carbonic anhydrase inhibitor. In Step 1 theappropriately substituted prostaglandin (76-1) is subjected to an acylchloride to afford a fully protected ester species (78-1). In Step 2 theappropriately substituted prostaglandin is subjected to thionyl chlorideas known in the art to afford an acyl chloride (78-2). In Step 3 theappropriately substituted acyl chloride is subjected to either an amineor alcohol to afford an amide or ester (78-3) respectively with aprotected aldehyde attached. In Step 4 the appropriately substitutedacetal is subjected to acid as known in the art to afford an aldehyde(78-4) which can be used in Scheme 79 to afford a compound of FormulaVII.

Scheme 79:

A compound of the present invention can be prepared, for example, from aprostaglandin and a carbonic anhydrase inhibitor. In Step 1 thepreviously prepared aldehyde (76-4) is subjected to a carbonic anhydraseinhibitor (CAI) (74-1) to afford a prostaglandin coupled to a CAIspecies (79-1). In Step 2 the appropriately substituted coupled speciesis desulfinated as known in the art to afford a compound (79-2) ofFormula VII.

Scheme 80:

A compound of the present invention can be prepared, for example, from aprostaglandin and a carbonic anhydrase inhibitor (CAI). In Step 1 theappropriately substituted CAI (74-1, 74-5) is subjected to an acylchloride of a prostaglandin (76-3) to afford an amide (80-1, 80-3). InStep 2 the appropriately substituted amide is deprotected to afford acompound (80-2, 80-4) of Formula VII.

Example 14. General Routes of Synthesis to Compounds of Formula VIII

Scheme 81:

A compound of the present invention can be prepared, for example, from aSunitinib derivative and either a prostaglandin or a carbonic anhydraseinhibitor (CAI). In Step 1 a commercially available Sunitinib precursor(81-1) is converted to a Sunitinib derivative (81-2) as known in theart. In Step 2 the synthetic handle (81-2) is converted to either analdehyde (to couple with a CAI) or a phenol (to couple with aprostaglandin) (81-3). In Step 3 the two compounds are covalently boundas known in the art to afford a compound (81-4) of Formula VIII.

Example 15. Representative Routes of Synthesis to Compounds of FormulaVIII

Scheme 82:

A compound of the present invention can be prepared, for example, from acarbonic anhydrase inhibitor (CAI) and a Sunitinib derivative. In Step 1the appropriately substituted carboxylic acid (82-1) is subjected toborane complexed with DMS to afford an alcohol (82-2). In Step 2 theappropriately substituted alcohol (82-2) is oxidized as known in the artto afford an aldehyde (82-3). In Step 3 the appropriately substitutedaldehyde (82-3) is subjected to ethylene glycol to afford a cyclicacetal (82-4). In Step 4 the appropriately substituted heterocycle(82-4) is subjected to an aldehyde (82-5) as known in the art to afforda conjugated alkene (82-6). In Step 5 the appropriately substitutedacetal (82-6) is deprotected with acid as known in the art to afford analdehyde (82-7). In Step 6 the appropriately substituted Sunitinibderivative (82-7) is subjected to a CAI (74-2) to afford a coupledspecies (82-8). In Step 7 the appropriately substituted species isdesulfinated as known in the art to afford an aldimine (82-9). In Step 8the appropriately substituted carbamate (82-9) is deprotected as knownin the art to afford a compound (82-10) of Formula VIII.

Scheme 83:

A compound of the present invention can be prepared, for example, from aprostaglandin and a Sunitinib derivative. In Step 1 the appropriatelysubstituted phenol (83-1) is subjected to a silyl chloride as known inthe art to afford a silyl ether (83-2). In Step 2 the appropriatelysubstituted heterocycle (82-2) is subjected to an aldehyde (82-5) asknown in the art to afford a conjugated alkene (83-3). In Step 3 theappropriately substituted silyl ether (83-3) is deprotected as known inthe art to afford a phenol (83-4). In Step 4 the appropriatelysubstituted Sunitinib derivative (83-4) is subjected to an acyl chlorideof a prostaglandin (76-3) to afford a coupled species (83-5) which upondeprotection is a compound (83-6) of Formula VIII.

Example 16. Representative Routes of Synthesis to Compounds of FormulaIX

Scheme 84:

A compound of the present invention can be prepared, for example, from aderivative of Crizotonib. In Step 1 the appropriately protectedpiperidine (84-1) is subjected to acidic conditions to remove the Bocgroup and afford an amine (84-2). In Step 2 the appropriatelysubstituted piperidine (84-2) is acylated as known in the art to affordan amide (84-3). In Step 3 the appropriately substituted halo-pyrazole(84-3) is subjected to a bis-boronic ester (84-4) as known in the art toafford a boronic ester (84-5). In Step 4 the appropriately substitutedboronic ester (84-5) is coupled with an aryl bromide (84-6) withcatalytic palladium to afford a protected derivative of Crizotinib(84-7) which is Boc-deprotected (84-8) to afford a compound of FormulaIX.

Example 17. Representative Routes of Synthesis to Compounds of Formula X

Scheme 85:

A compound of the present invention can be prepared, for example, from aderivative of KW-2449. In Step 1 the appropriately mono-protectedpiperazine (85-1) is acylated as known in the art to afford an amide(85-2). In Step 2 the appropriately substituted piperazine (85-2) issubjected to acidic conditions to remove the Boc group and afford anamine (85-3). In Step 3 the appropriately substituted amine (85-3) iscoupled to an aryl carboxylic acid (85-4) as known in the art to afforda compound (85-5) of Formula X.

Example 18. Representative Routes of Synthesis to Compounds of FormulaXI

Scheme 86:

A compound of the present invention can be prepared, for example, fromvarious piperidino based DLK inhibitors. In Step 1 the boronic ester(86-1) as described in the literature is coupled to an aryl iodide(86-2) in the presence of catalytic palladium to afford a heterocycle(86-3). In Step 2 the appropriately substituted aryl chloride (86-3) issubjected to nucleophilic conditions as known in the art to afford afunctionalized aryl chloride (86-5). In Step 3 the appropriatelysubstituted aryl chloride (86-5) is subjected to nucleophilic conditionsagain as known in the art to afford a complex species (86-7). In Step 4the appropriately substituted piperidino double bond is reduced withpalladium catalyst to afford a protected piperidine species (86-8). InStep 5 the appropriately substituted piperidine species (86-8) issubjected to acidic conditions to remove the Boc group and afford anamine (86-9). In Step 6 the appropriately substituted amine (86-9) isacylated as known in the art with a variety of acyl chlorides to afforda compound (86-10) of Formula XI.

Example 19. Representative Routes of Synthesis to Compounds of FormulaXII

Scheme 87:

A compound of the present invention can be prepared, for example, from aderivative of Tozasertib. In Step 1 the appropriately mono-protectedpiperazine (85-1) is acylated as known in the art to afford an amide(85-2). In Step 2 the appropriately substituted piperazine (85-2) issubjected to acidic conditions to remove the Boc group and afford anamine (85-3). In Step 3 the appropriately substituted amine (85-3) issubjected to an aryl chloride (87-1) as known in the art to afford acompound (87-2) of Formula XII.

Example 20. Non-Limiting Examples of Compounds of Formula I

Example 21. Non-Limiting Examples of Compounds of Formula II

Example 22. Non-Limiting Examples of Compounds of Formula III, FormulaIV, Formula V, and Formula VI

Example 23. Non-Limiting Examples of Compounds of Formula VII

Example 24. Non-Limiting Examples of Compounds of Formula VII′

Example 25. Non-Limiting Examples of Compounds of Formula VIII

Example 26. Non-Limiting Examples of Compounds of Formula IX

Example 27. Non-Limiting Examples of Compounds of Formula X

Example 28. Non-Limiting Examples of Compounds of Formula XI

Example 29. Non-Limiting Examples of Compounds of Formula XII

Example 30. Non-Limiting Examples of Compounds of Formula XIV

Example 31. Non-Limiting Examples of Compounds of Formula XV

Example 32. Non-Limiting Examples of Compounds of Formula XVI

Example 33. Non-Limiting Examples of Compounds of Formula XVII

Example 34. Analytical Method Development for Compounds ContainingCarbonic Anhydrase Inhibitors (CAIs) Determination of Maximal AbsorptiveWavelength

Solutions of brinzolamide and dorzolamide and their covalent conjugatesof polylactic acid (PLA) were individually prepared in methanol at aconcentration of 100 μg/mL. The samples were scanned at a wavelengthrange of 200-800 nm using a Genesys 105 UV-VIS spectrophotometer (ThermoScientific). From the respective absorption spectra, 254 nm was selectedas the detection wavelength for brinzolamide, dorzolamide and their PLAconjugates.

HPLC Method for Brinzolamide, Dorzolamide and their PLA Conjugates

A reversed phase performance liquid chromatographic method was developedfor the simultaneous determination of brinzolamide or dorzolamide andtheir conjugates with varying PLA. Successful chromatographic separationwas achieved using an Agilent 1260 Infinity HPLC equipped with a diodearray and a multiple wavelength detector with an XTERRA C8 column (5 μm,4.6 mm×150 mm) as the stationary phase. The mobile phase consisted of a5-95% acetonitrile (MeCN) gradient over 4 minutes followed by a secondrapid gradient change of MeCN concentration from 95% to 5% between 5 and5.5 min (Table 1). The flow rate was 1.0 mL/min and the detectionwavelength was 254 nm. The injection volume was 10 μL. The analysis wasperformed at 25° C. Both water and MeCN contained 0.1% (v/v) formic acid(FA). Retention times are illustrated in Table 2. From the overlay ofthe individual chromatograms, the method provides adequate resolutionfor chromatographic separation of parent and PLA conjugated compoundswith different numbers of lactic acid (LA) units and functionalend-groups.

TABLE 1 HPLC gradient for separation of brinzolamide, dorzolamide andtheir PLA-conjugates A (water + B (MeCN + Time (min) 0.1% FA) 0.1% FA) 095 5 4 5 95 5 5 95 5.5 95 5 7 95 5

TABLE 2 Relative retention times (RRT) of brinzolamide, dorzolamide andtheir PLA-conjugates PLA Repeat Units Brinzolamide RRT (min) DorzolamideRRT (min) Parent 3.64 2.95 n = 1 3.91 3.65 n = 2 4.07 — n = 3 4.18 4.00n = 4 4.35 4.20 Acetyl, n = 3 4.53 4.45 Acetyl, n = 4 4.72 4.60 Acetyl,n = 5 4.90 4.78 Acetyl, n = 6 5.05 4.98 n is the number of LA repeatunits conjugated to the parent compound

Example 35. Analytical Method Development for Compounds ContainingLatanoprost Determination of Maximal Absorptive Wavelength

Latanoprost and latanoprost-Acetyl PLA conjugates were dissolved in DMSOat a concentration of 100 μg/mL. The samples were scanned at awavelength range of 200-800 nm using a Genesys 105 UV-VISspectrophotometer (Thermo Scientific). From the respective absorptionspectra, 210 nm was selected as the detection wavelength.

HPLC Method for Latanoprost and PLA-Conjugated Latanoprost

Chromatographic separation of latanoprost parent compound and its PLAconjugated derivatives was achieved using an Agilent 1260 Infinity HPLCequipped with a diode array and a multiple wavelength detector with anXTERRA C₈ column (5 μm, 4.6 mm×150 mm) as the stationary phase. Thegradient separation method is outlined in Table 3. The analysis wasperformed at an injection volume of 50 μL, a flow rate of 1.2 mL/min anda detection wavelength of 210 nm at 25° C. Retention times forlatanoprost and PLA-conjugated compounds are illustrated in Table 4.

TABLE 3 HPLC gradient method for separation of latanoprost derivatives B(MeCN + 0.1% Time (min A (water + 0.1% FA) FA) 0 95 5 6 40 60 7 5 95 8 595 9 95 5 15 95 5

TABLE 4 Relative retention times of latanoprost and its derivatives PLARepeat Units RRT (min) Parent 9.66 Acetyl, n = 3 10.15 Acetyl, n = 410.48 Acetyl, n = 5 10.71 n is the number of LA repeat units conjugatedto the parent compound.

Example 36. Determination of Drug Solubility

For each test, approximately 5-10 mg was transferred to a 10 mL glassvial. Aqueous or organic solvent was added to each vial to achieve anoverall concentration of 50 mg/mL. After vortexing aggressively for 2-3minutes and sonicating in a bath sonicator for 5 minutes, undissolveddrug was spun down at 1200 rpm for 5 minutes to generate a pellet. Thesupernatant was collected and filtered through a 0.2 m nylon syringefilter into HPLC vials for drug content analysis. Drug concentration wasdetermined by comparing against a standard calibration curve.

Solubility of Compounds Containing Brinzolamide, Dorzolamide orLatanoprost

Drug solubility in aqueous and organic solvent can inform on thepotential for said drug to be encapsulated within microparticles and itsrelease kinetics once it has been encapsulated. Herein, drug solubilitywas evaluated to better predict and select compounds that may beamenable to particle encapsulation. As demonstrated in Table 5,brinzolamide exhibits low aqueous solubility (<1 mg/mL), but highsolubility in DMSO (>50 mg/mL), whereas dorzolamide is characterized byhigh aqueous solubility and low organic solubility. Interestingly,chemical modification by the addition of a short PLA (n=2-4) via anamide linkage to the sulfonamide nitrogen significantly increased theaqueous solubility of brinzolamide from <1 mg/mL to >50 mg/mL,respectively. However, when the terminal lactate is acetylated and thenumber of LA repeat units is greater than 3, the aqueous solubility ofbrinzolamide conjugates remains low (<1 mg/mL). Chemical modification ofdorzolamide significantly enhanced the organic solubility of dorzolamideonly when the number of LA units exceeded 3 or when the terminal unitwas acetylated. Aqueous solubility of dorzolamide was significantlydecreased from >50 mg/mL to <1 mg/mL when conjugated to PLA (n>3) andcapped with an acetyl group.

Similar to brinzolamide, latanoprost exhibited very low aqueoussolubility and high organic solubility. Conjugation of PLA andacetylation of the terminal lactate unit did not significantly alter itsaqueous solubility, but did decrease its organic solubility from greaterthan 50 mg/mL to less than 25 mg/mL.

All bifunctional conjugates with sunitinib exhibited low aqueoussolubility and high organic solubility (less than 1 mg/mL in aqueoussolution and greater than 50 mg/mL in DMSO), respectively.

TABLE 5 Solubility of brinzolamide, dorzolamide, latanoprost and theirPLA conjugates Solubility Compound Water DMSO DCM Compound number(mg/mL) (mg/mL) (mg/mL) Brinzolamide Brinzolamide <1.0 >50 <7.5Brinzolamide-PLA (n = 2) 33-2 >50 >50 >50 Brinzolamide-PLA (n = 3)34-2 >50 >50 >50 Brinzolamide-PLA (n = 4) 35-2 >50 >50 >50Brinzolamide-Acetyl PLA (n = 3) 36-1 >50 >50 >50 Brinzolamide-Acetyl PLA(n = 4) 37-1 <1.0 >50 >50 Brinzolamide-Acetyl PLA (n = 5) 38-1<1.0 >50 >50 Brinzolamide-Acetyl PLA (n = 6) 39-1 <1.0 >50 >50Dorzolamide Dorzolamide >50 <1.0 <1.0 Dorzolamide-PLA (n = 3) 20-2 >50<2.0 <5.0 Dorzolamide-PLA (n = 4) 21-2 >50 >50 >50 Dorzolamide-AcetylPLA (n = 3) 26-1 >50 >50 >50 Dorzolamide-Acetyl PLA (n = 4) 27-1<1.0 >50 >50 Dorzolamide-Acetyl PLA (n = 5) 28-1 <1.0 >50 >50Dorzolamide-Acetyl PLA (n = 6) 29-1 <1.0 >50 >50 Latanoprost Latanoprost<1.0 >50 >50 Latanoprost-Acetyl PLA (n = 3) 43-2 <1.0 <25 —Latanoprost-Acetyl PLA (n = 4) 44-1 <1.0 <25 — Latanoprost-Acetyl PLA (n= 5) 45-1 <1.0 <50 — 5-Amino sunitinib 47-1 <1.0 >50 — Dorzolamide-PLA(n = 3)- 57-3 <1.0 >50 — succinate-5-amino sunitinib Dorzolamide-PLA (n= 3)- 56-5 <1.0 >50 — succinate-5-hydroxy sunitinib Dorzolamide-PLA (n =4)- 58-5 <1.0 >50 — succinate-5-hydroxyl sunitinib Brinzolamide-PLA (n =4)- 60-1 <1.0 >50 — succinate-5-hydroxy sunitinib 5-hydroxylsunitinib-PLA (n = 3)- 54-1 <1.0 >50 — Etacrynic acid Brinzolamide-PLA(n = 3)-adipate- 61-3 <1.0 >50 — 5-hydroxyl sunitinib (isomer-1)Brinzolamide-PLA (n = 3)-adipate- 61-2 <1.0 >50 — 5-hydroxyl sunitinib(isomer-2)

Example 37. In Vitro Stability In Vitro Stability of Brinzolamide NCEs

Brinzolamide and brinzolamide-PLA NCEs were first dissolved in PBS (pH7) containing 10% DMSO (v/v) at a concentration of 1 mg/mL. The sampleswere incubated at 37° C. or 50° C. to simulate physiological andaccelerated degradation conditions, respectively. At various timepoints, 100 μL of the solution was collected, diluted 10-fold withMeCN+0.1% formic acid, filtered through a 0.2 μm nylon syringe filterand analyzed by RP-HPLC.

As shown in FIG. 1, brinzolamide remained relatively stable across the14 day incubation period at physiological and accelerated conditions.Similarly, the prodrug brinzolamide-PLA (n=1) (32-3) demonstrated highstability in vitro at 37° C. with >98% of the primary compound remainingat 14 days (FIG. 2). Increase in the length of PLA chain resulted in anincrease in the degradation rate of the primary compound with loss ofPLA monomers. As shown in FIG. 3, the linkage between LA 1 and 2 inbrinzolamide-PLA (n=2) (33-2) is relatively stable, but it breaks downover time, and approximately 53% of the primary compound remained afterthe 14 day incubation period. FIG. 4 shows the degradation profile ofbrinzolamide-PLA (n=3) (34-2). As the n=1 amide bond is highly stable,minimal degradation to the parent compound was detected at the end ofthe 19 day incubation. Interestingly, as the number of LA repeat unitsincreased to 4, the propensity of the LA units to hydrolyze in pairs wasclearly evident. As shown in FIG. 5, the primary compound rapidly loseslactate units in pairs to generate brinzolamide-PLA (n=2) (33-2). Afteronly one day of incubation at 37° C., approximately 93% of the primarycompound (brinzolamide-PLA (n=4) (35-2)) had degraded tobrinzolamide-PLA (n=2) (33-2).

As illustrated in FIG. 6, capping the terminal hydroxyl with an acetylgroup enhances the stability of the primary compound in vitro over theuncapped derivative. At day 7, approximately 2.7% of the primarybrinzolamide-PLA (n=3) (34-2) remained, whereas in comparison,approximately 15.4% of brinzolamide-acetyl PLA (n=3) (36-1) remained atday 7. Additionally, substitution of the acetyl end group with a butylgroup resulted in a significant increase in the stability of thecompound. As shown in FIG. 7, the degradation kinetics of the primarybrinzolamide-t-butyl PLA (n=3) (40-1) was significantly slower than itsacetylated (36-1) or uncapped counterpart (34-2). FIG. 8, FIG. 9, andFIG. 10 reinforce the idea that lactate units are cleaved in pairs.

In summary, the kinetics of hydrolysis is slowest for brinzolamide-PLA(n=1) (32-3), followed by the t-butyl and O-acetyl terminatedderivatives, with the —OH terminated derivatives exhibiting the fastestrate of degradation. Under 50-60° C. incubation, the rate of degradationincreased rapidly, yet similar trends in the kinetic of degradation wereobserved. For example, the tendency for hydrolysis to occur in pairs oflactate and the enhanced stability afforded by t-butyl and O-acetylcapped compounds over uncapped compounds was still prominent underaccelerated conditions (data not shown).

In Vitro Stability of Dorzolamide NCEs

The in vitro stability of dorzolamide and PLA conjugated NCEs wereevaluated using the same method as that described above for brinzolamideand its derivatives. Similar to brinzolamide, dorzolamide was found tobe highly stable with minimal degradation at 37° C. and 60° C. for up to14 days (FIG. 11). The kinetics of degradation of dorzolamide NCEs werecomparable to those observed with the brinzolamide NCEs; dorzolamide-PLA(n=1) (19-3) was the most stable, followed by O-acetyl derivatives, anduncapped derivatives with —OH were the least stable. Similarly, it wasclear that the LA units were hydrolyzed in pairs (FIG. 12, FIG. 13, FIG.14, FIG. 15, and FIG. 16). Under accelerated conditions (50° C.), therate of degradation rapidly increased, yet the trends in degradationkinetics remained the same as the degradation kinetics at 37° C. (datanot shown).

In Vitro Stability of Latanoprost NCEs

Latanoprost and latanoprost-PLA conjugates were solubilized with theaddition of 20% (v/v) DMSO and subsequently suspended to a concentrationof 1 mg/mL in PBS (pH 7.0). The samples were incubated at 37° C. and atvarious time points, aliquots were collected, diluted 10-fold withMeCN:water (1:1), filtered through a 0.2 μm nylon syringe filter, andanalyzed by RP-HPLC.

Similar to brinzolamide and dorzolamide, the prostaglandin agonistexhibited good stability throughout the 14 day incubation period. Theprodrugs of latanoprost exhibited the same preferential tendency to loselactate units in pairs.

In Vitro Stability of Bifunctional Conjugates

The in vitro stability of the bifunctional conjugates of brinzolamide ordorzolamide with sunitinib was evaluated through analysis of thepresence or absence of the signal corresponding to the carbonicanhydrase inhibitor at 254 nm. Briefly, brinzolamide-PLA(n=4)-succinate-5-hydroxy-sunitinib (60-1) or dorzolamide-PLA(n=4)-succinate-5-hydroxy-sunitinib (58-5) was first dissolved in asolution of PBS (pH 7.0) with 20% DMSO (v/v) and incubated at 37° C. or60 OC for 14 days. At various time points, 100 uL of the solution wascollected, diluted 10-fold with MeCN:water (1:1), filtered through a 0.2μm syringe filter, and analyzed on an HPLC at a detection wavelength of254 nm.

The degradation kinetic of brinzolamide-PLA(n=4)-succinate-5-hydroxy-sunitinib (60-1) at 37° C. and 60° C. ispresented in FIG. 23 A and FIG. 23B, respectively. At 1 day, the primarybioconjugate was rapidly hydrolyzed, resulting in the generation ofbrinzolamide-PLA with 1-3 lactate units. The PLA (n=4) signal decreasedfrom 83% to 15.7% after one day of incubation. At 37° C., the generationand degradation of brinzolamide-PLA (n=3) remained relatively staticover the time course of the experiment, whereas the amount ofbrinzolamide-PLA (n=2) and brinzolamide-PLA (n=1) increased over time.In contrast, under elevated temperature, the rate of degradation tobrinzolamide-PLA (n=1) was significantly faster than that atphysiological temperature. Similar degradation kinetics can be observedfor dorzolamide-PLA (n=4)-succinate-5-hydroxy-sunitinib (58-5) withdegradation of the primary dorzolamide-PLA (n=4) signal rapidlydecreasing after one day. However, in contrast to the brinzolamide-PLA(n=4)-succinate-5-hydroxy-sunitinib (60-1) bioconjugate, the primarysite of hydrolysis for dorzolamide-PLA(n=4)-succinate-5-hydroxy-sunitinib (58-5) was between the first andsecond lactate units, which resulted in the rapid generation ofdorzolamide-PLA (n=1).

Example 38. Bioactivity of Conjugates of Carbonic Anhydrase Inhibitors(CAIs)

The generation of aqueous humor is dependent on the production ofbicarbonate from carbonic anhydrase isoenzyme II, which is abundantlyfound in non-pigmented ciliary body epithelium. Carbonic anhydrase (CA)catalyzes the reversible hydration of carbon dioxide to carbonic acid,which subsequently dissociates to form protons and bicarbonate anions.Increase in bicarbonate affects fluid transport dynamics indirectlythrough Na⁺ regulation. Carbonic anhydrase inhibitors actively blockcarbonic anhydrase activity, which results in reduced production ofbicarbonate ions and thus decreases fluid transport resulting indecreased intraocular pressure.

The brinzolamide- and dorzolamide-PLA monofunctional conjugates andbifunctional conjugates were screened for their carbonic anhydraseinhibitory potential. The catalytic activity of carbonic anhydrase IIwas assessed by a colorimetric method, in which 4-nitrophenyl acetate ishydrolyzed to acetate and nitrophenolate. The nitrophenolate ionizes togenerate a bright yellow anion that is readily detected by measuring itsabsorbance at 350-400 nm. Briefly, 140 μL of assay solution (HEPES andTris buffer solution (20 mM, pH 7)) was dispensed into Eppendorf tubesand purified bovine erythrocyte carbonic anhydrase II (20 μL, 0.1 mg/mLin purified water) was added to the vial. Subsequently, 20 μL of thetest compound (0.01-1000 nM) dissolved in DMSO was added to the reactionvial and allowed to equilibrate for 15 minutes with the enzyme.Acetazolamide was added as a positive control and 100% DMSO was added asa negative control. The reaction was initiated with the addition of 20μL of 4-nitrophenyl acetate (0.7 mM in ethanol). The absorbance wasmeasured at 400 nm for 15 minutes using a Genesys 105 UV-VISspectrophotometer (Thermo Scientific). (DMSO did not interfere with thelevel of CA activity or specificity in this assay.) The assay wasconducted in triplicate and the normalized data was analyzed usingGraphPad Prism version 4.0 and fit to a 4-parameter non-linear sigmoidaldose-response model to generate IC₅₀ values.

The parent compounds demonstrated the highest inhibition of carbonicanhydrase activity. Increasing the length of the LA units resulted in areduction of bioactivity (Table 6). In addition, capping the terminalgroup of PLA with an acetyl group did not significantly alter thebioactivitity of the compound. The IC₅₀ for brinzolamide-PLA (n=3)(34-2) vs brinzolamide-acetyl PLA (n=3) (36-1) was 21.5±11.2 vs.20.7±9.54, respectively. However, all tested compounds maintainedrelatively high bioactivity within the nanomolar range. Bioconjugates ofbrinzolamide- or dorzolamide-PLA with sunitinib (60-1, 58-5, 57-3 &56-5) exhibited the lowest inhibitory activity, possibly owing to sterichindrance of sunitinib and PLA conjugated to the CAIs.

TABLE 6 Bioactivity of conjugates containing CAIs Compound IC₅₀ Compoundnumber (nM, n = 2) Brinzolamide Brinzolamide 5.21 ± 4.14Brinzolamide-PLA (n = 1) 32-3 5.78 ± 3.78 Brinzolamide-PLA (n = 2) 33-210.7 ± 7.27 Brinzolamide-PLA (n = 3) 34-2 21.5 ± 11.2Brinzolamide-Acetyl PLA (n = 3) 36-1 20.7 ± 9.54 Brinzolamide-Acetyl PLA(n = 4) 37-1 41.5 ± 11.2 Brinzolamide-Acetyl PLA (n = 5) 38-1 102.1 ±31.4  Brinzolamide-Acetyl PLA (n = 6) 39-1 171.6 ± 35.6  DorzolamideDorzolamide 1.35 ± 0.64 Dorzolamide-PLA (n = 1) 19-3 3.32 ± 2.71Dorzolamide-PLA (n = 3) 20-2 14.1 ± 5.07 Dorzolamide-PLA (n = 4) 21-248.5 ± 10.5 Dorzolamide-Acetyl PLA (n = 3) 26-1 16.4 ± 7.25Dorzolamide-Acetyl PLA (n = 4) 27-1 44.1 ± 14.8 Dorzolamide-Acetyl PLA(n = 5) 28-1 89.2 ± 18.1 Dorzolamide-PLA (n = 3)-succinate-5- 57-3 195.1± 45.3  hydroxy sunitinib Dorzolamide-PLA (n = 3)-succinate-5- 56-5184.5 ± 44.8  amino sunitinib Dorzolamide-PLA (n = 4)-succinate-5- 58-5221.6 ± 36.3  hydroxy sunitinib Brinzolamide-PLA (n = 4)-succinate-5-60-1 247.4 ± 49.12 hydroxy sunitinib IC₅₀ - half-maximal inhibitoryconcentration

Example 39. Encapsulation of Conjugates in Polymer MicroparticlesMaterials

poly(D,L-lactic-co-glycolic acid (PLGA, 75:25 lactic acid to glycolicacid ratio, 4 A, Evonik)poly(D,L-lactic-co-glycolic acid (PLGA, 50:50 lactic acid to glycolicacid ratio)-poly(ethylene glycol)5000poly vinyl alcohol (Mr˜25K, 88% hydrolyzed, Polysciences)D-α-tocopherol poly(ethylene glycol)₁₀₀₀ succinate (Sigma Aldrich)Phosphate-buffered saline (pH 7.4)Ultrapure cell culture grade waterAll other chemicals were A.C.S. reagent grade (VWR)

Microparticle Preparation

Microparticles containing prodrugs of brinzolamide or dorzolamide-PLAwere formulated using an oil-in-water solvent evaporationmicroencapsulation method. The polymer was initially dissolved in awater immiscible organic solvent to which dissolved drug was added.Briefly, 280 mg of PLGA (LA:GA=75:25, 4 A) and 2.8 mg ofPLGA_(50/50)-PEG5k was dissolved in 2 mL of methylene chloride. The CAI(45 mg) was dissolved in 1 mL of DMSO after vigorous vortexing andultrasonication in a bath sonicator and added to the polymer solution.The aqueous phase consisted of 200 mL of PBS with 1% PVA orD-α-tocopherol poly(ethylene glycol)₁₀₀₀ succinate as a surfactant tostabilize the emulsification. The aqueous phase was mixed at 5000 rpmsusing a Silverson L5A-M benchtop mixer. The dispersed phase was rapidlyadded to the aqueous phase and allowed to mix at 5000 rpms for 1 minuteto generate an oil-in-water emulsion and disperse the materials asdroplets. The organic solution was allowed to evaporate under constantstirring at 500 rpms for 2 hours at 25° C. or at 4° C. in an ice bath.The particle suspension was allowed to settle for 30 min, after whichthe solution was decanted and remaining particles were collected,suspended in distilled deionized water, and washed 3 times using watervia centrifugation at 1000 rpms for 5 minutes to remove any residualsolvent. The pellet was collected and lyophilized overnight.

Particle Size Analysis

Particle size and size distribution was determined using a BeckmanCoulter Multsizer IV with a 100 μm diameter aperture based on a samplesize of at least 50,000 counts. Particle size is expressed asvolume-weighted mean diameters. Briefly, 2-5 mg of particles weresuspended in 1 mL of double distilled water and added to a beakercontaining 100 mL of ISOTON II solution. Measurements were obtained oncethe coincidence of particles reached 6-10%. Table 7 outlines the sizeand size distribution of the microparticles generated for each testcompound. Particle size can vary depending upon a number of variablesincluding polymer concentration, mixing-speed, mixing-time,dispersed/aqueous phase ratio, etc. Particles were formulated withvolume-weighted mean diameters ranging from approximately 18 μm to 28 μmdepending on the formulation parameters.

TABLE 7 Particle size of microparticles encapsulating drug conjugates*Particles were generated at room temperature with 1% PVA as asurfactant in the aqueous phase Compd Mean Compound # (μm) SD d10 d50d90 brinzolamide-PLA (n = 4) 35-2 23.0 7.48 11.9 20.8 38.4dorzolamide-PLA (n = 4) 21-2 23.0 8.53 13.3 21.8 21.8brinzolamide-Acetyl 37-1 24.9 8.27 17.2 25.0 32.6 PLA (n = 4)dorzolamide-Acetyl 27-1 26.4 8.94 18.3 26.3 34.1 PLA (n = 4)brinzolamide-Acetyl 38-1 23.0 7.73 11.9 20.8 38.4 PLA (n = 5)dorzolamide-Acetyl 28-1 23.0 8.06 13.3 21.8 34.8 PLA (n = 5)dorzolamide-Acetyl 28-1 17.9 6.49 9.69 16.3 34.8 PLA (n = 5, no DMSO)latanoprost-Acetyl 44-1 28.1 8.58 16.6 26.5 41.6 PLA (n = 4)¹brinzolamide-Acetyl 38-1 26.5 7.98 18.4 25.9 36.6 PLA (n = 5)²brinzolamide-Acetyl 38-1 27.4 7.86 17.2 27.4 37.9 PLA (n = 5)¹dorzolamide-Acetyl 28-1 19.7 9.45 8.88 18.3 31.1 PLA (n = 5)¹latanoprost-Acetyl 45-1 26.44 9.18 12.2 27.5 38.2 PLA (n = 5)¹Particles generated at 4° C. with D-α-tocopherol poly(ethyleneglycol)₁₀₀₀ succinate as the surfactant. ²Particles generated at 4° C.with D-α-tocopherol poly(ethylene glycol)₁₀₀₀ succinate as thesurfactant with increased polymer concentration (200 mg/mL).

Drug Loading

To determine the % drug loading (DL), 10 mg of particles was weighedinto a glass scintillation vial and dissolved with 10 mL of MeCN:water(1:1, v/v). The solution was filtered through a 0.2 μm nylon syringefilter and the drug content was determined by RP-HPLC referenced againsta standard calibration curve. The drug loading results are presented inTable 8. Interestingly, all particles generated at 25° C. with 1% PVA inthe aqueous phase exhibited low drug loading regardless of theencapsulated drug (<1.0% DL), but results in Table 8 suggest thatloading is influenced by the presence of the functional group on theterminal lactate. Loading of acetylated test compounds was approximately5-fold higher than those with uncapped hydroxyl on the terminal lactateunits (0.14 vs. 1.00 and 0.22 vs. 0.98%, respectively for brinzolamideand dorzolamide).

Loading was also dependent on the rate of solidification of theparticles and the surfactant used in the emulsification process.Preparing particles at 4° C. and with D-α-tocopherol poly(ethyleneglycol)₁₀₀₀ succinate to stabilize the emulsification resulted insignificant enhancement in drug loading. For example, % DL ofbrinzolamide-acetyl PLA (n=5) (38-1) was 0.73% when particles wereformulated at room temperature using 1% PVA as the surfactant comparedto 7.39% when particles were formulated at 4° C. using D-α-tocopherolpoly(ethylene glycol)₁₀₀₀ succinate as the surfactant. In addition,increasing polymer concentration also resulted in a nominal increase in% DL. Brinzolamide-acetyl PLA (n=5) (38-1) content increased from 7.39%to 8.89% when the polymer concentration increased from 140 mg/mL to 200mg/mL, respectively.

TABLE 8 Drug loading of microparticles encapsulating the drug conjugatesCompound Compound number % DL brinzolamide-PLA (n = 4) 35-2 0.14dorzolamide-PLA(n = 4) 21-2 0.22 brinzolamide-Acetyl PLA(n = 4) 36-11.00 dorzolamide-Acetyl PLA(n = 4) 27-1 0.98 brinzolamide-Acetyl PLA(n =5) 38-1 0.73 dorzolamide-Acetyl PLA(n = 5) 28-1 0.92 dorzolamide-AcetylPLA(n = 5, 28-1 0.82 no DMSO) latanoprost-Acetyl PLA(n = 4) 44-1 0.53¹brinzolamide-Acetyl PLA(n = 5) 38-1 7.39 ²brinzolamide-Acetyl PLA(n =5) 38-1 8.89 ¹dorzolamide-Acetyl PLA(n = 5) 28-1 8.71¹latanoprost-Acetyl PLA(n = 5) 45-1 3.57 ¹Particles generated at 4° C.with D-α-tocopherol poly(ethylene glycol)₁₀₀₀ succinate as thesurfactant. ²Particles generated at 4° C. with D-α-tocopherolpoly(ethylene glycol)₁₀₀₀ succinate as the surfactant with increasedpolymer concentration (200 mg/mL).

Particle Morphology

Particle morphology was assessed using a Nikon Eclipse TS-100 lightmicroscope. Briefly, 3-5 mg of particles were suspended in 1 mL ofwater. A volume of 10 uL of the particle suspension was transferred ontoa glass slide and imaged directly. In general, particles were found tobe spherical in morphology (FIG. 25A, FIG. 25B, FIG. 25C, and FIG. 25D).

Drug Release

In vitro drug release kinetics was evaluated in a release medium of PBSand 1% Tween 20 (pH 7.4). Briefly, 10 mg of particles were transferredto glass scintillation vials and 4 mL of the release medium was added tosuspend the particles. Samples were prepared in duplicate. The particleswere mixed by gentle vortexing and incubated on an orbital shaker at 150rpm at 37° C. At various time points, 3 mL of release media wascollected and analyzed for drug content and 3 mL of fresh media wasadded to replace the sample that was collected. Collected releasesamples were frozen and stored at −80° C. until analysis for drugcontent. The collected samples were filtered through a 0.2 μm syringefilter and analyzed by RP-HPLC.

FIG. 26 illustrates the cumulative release profile for particlesencapsulating brinzolamide-acetyl PLA (n=5) (38-1). The cumulativerelease profiles of both formulations exhibited relatively low burstrelease (0.62% and 0.20% released at 3 hours, respectively). At 13 days,the release profile with particles formulated with a polymerconcentration of 140 mg/mL (% DL=7.39) was relatively linear, althoughthe overall release rate was slightly higher than for particles preparedat a higher polymer concentration (200 mg/mL, % DL=8.89). At 13 days,approximately 21-23% of the drug had been released from the particles.The rate of release of brinzolamide-acetyl PLA (n=5) (38-1) may beattributed to its high hydrophobicity and hydrophobic interactionsbetween the drug and the polymer matrix. Increasing the hydrophobicityof the polymer by selecting a higher LA:GA ratio polymer or PLA mayfurther decrease the rate of release.

In vitro release profiles of dorzolamide-acetyl PLA (n=5) (28-1) andlatanoprost-acetyl PLA (n=5) (45-1) are shown in FIG. 27. The releasekinetics for dorzolamide-acetyl PLA (n=5) (28-1) is significantly fasterthan latanoprost-acetyl PLA (n=5) (45-1); approximately 6.86% ofdorzolamide-acetyl PLA (n=5) (28-1) released after 6 days compared to1.67% for latanoprost-acetyl PLA (n=5) (45-1). This may be attributed tothe differences in hydrophobicity between the CAIs and latanoprost.Burst release was also significantly higher for dorzolamide-acetyl PLA(n=5) (28-1) than latanoprost-acetyl PLA (n=5) (45-1). At 3 hours,approximately 1.17% of dorzolamide-acetyl PLA (n=5) (28-1) had beenreleased compared to 0.15% for latanoprost-acetyl PLA (n=5) (45-1). Themicroparticle compositions described herein have demonstrated thepotential to load and release one or more prodrugs for the management ofelevated intraocular pressure for a prolonged period.

Example 40. Non-Limiting Examples of Compounds of Formula I, II, III,IV, XIV, XV, XVI, and XVII

Table 9 shows illustrative compounds of Formula I, II, III, IV, XIV, XV,XVI, and XVII with characterizing data.

TABLE 9 Non-limiting Examples of Synthesized Compounds Comp. # Structure19-3

20-2

21-2

22-2

23-2

24-2

25-2

26-1

27-1

28-1

29-1

30-1

31-1

32-3

33-2

34-2

35-2

36-1

37-1

38-1

39-1

40-1

41-1

42-1

43-2

44-1

45-1

46-1

47-3

48-3

49-1

50-1

51-1

52-1

53-2

54-1

55-4

56-5

57-3

58-5

59-1

60-1

61-2

61-3

This specification has been described with reference to embodiments ofthe invention. However, one of ordinary skill in the art appreciatesthat various modifications and changes can be made without departingfrom the scope of the invention as set forth herein. Accordingly, thespecification is to be regarded in an illustrative rather than arestrictive sense, and all such modifications are intended to beincluded within the scope of invention.

What is claimed is:
 1. A compound of Formula XV:

or a pharmaceutically acceptable salt thereof; wherein: R³² is R³⁵; R³⁵is selected from

R⁵¹ is

R¹⁵ is R¹⁷; R¹⁷ is selected from H and —C(O)A; A is selected from H,alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, and alkyloxy; and x andy are independently selected from an integer between 1 and
 30. 2. Thecompound of claim 1, wherein x and y are independently selected from 1,2, 3, 4, 5, or
 6. 3. The compound of claim 2, wherein x is 1 and y isselected from 1, 2, 3, or
 4. 4. The compound of claim 2, wherein x is 2and y is selected from 1, 2, 3, or
 4. 5. The compound of claim 3,wherein x is 1 and y is
 3. 6. The compound of claim 3, wherein x is 1and y is
 4. 7. The compound of claim 1, wherein R⁵¹ is


8. The compound of claim 7, wherein R¹⁵ is hydrogen.
 9. The compound ofclaim 1, wherein R³⁵ is


10. The compound of claim 9, wherein R⁵¹ is


11. The compound of claim 10, wherein R¹⁵ is hydrogen.
 12. The compoundof claim 11, wherein x and y are independently selected from 1, 2, 3, or4.
 13. The compound of claim 12, wherein x is 1 or 2 and y is selectedfrom 2, 3, or
 4. 14. The compound of claim 13, wherein x is 2 and y is3.
 15. The compound of claim 13, wherein x is 2 and y is
 4. 16. Thecompound of claim 13, wherein x is 1 and y is
 3. 17. The compound ofclaim 13, wherein x is 1 and y is
 4. 18. The compound of claim 1,wherein R³¹ is


19. The compound of claim 18, wherein R⁵¹ is


20. The compound of claim 19, wherein R¹⁵ is hydrogen.
 21. The compoundof claim 20, wherein x and y are independently selected from 1, 2, 3, or4.
 22. The compound of claim 21, wherein x is 1 or 2 and y is selectedfrom 2, 3, or
 4. 23. The compound of claim 22, wherein x is 2 and y is3.
 24. The compound of claim 22, wherein x is 2 and y is
 4. 25. Thecompound of claim 22, wherein x is 1 and y is
 3. 26. The compound ofclaim 22, wherein x is 1 and y is
 4. 27. The compound of claim 1 of theformula

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1 of the formula

or a pharmaceutically acceptable salt thereof.
 29. The compound of claim1 of the formula

or a pharmaceutically acceptable salt thereof.
 30. The compound offormula

or a pharmaceutically acceptable salt thereof.
 31. A pharmaceuticalcomposition comprising a compound of claim 1 in a pharmaceuticallyacceptable carrier.
 32. A pharmaceutical composition comprising acompound of claim 27 in a pharmaceutically acceptable carrier.
 33. Apharmaceutical composition comprising a compound of claim 28 in apharmaceutically acceptable carrier.
 34. A pharmaceutical compositioncomprising a compound of claim 29 in a pharmaceutically acceptablecarrier.
 35. A pharmaceutical composition comprising a compound of claim30 in a pharmaceutically acceptable carrier.
 36. A method for thetreatment of an ocular disorder treatable with both a tyrosine kinaseinhibitor and a carbonic anhydrase inhibitor comprising administering atherapeutically effective amount of a compound or pharmaceuticallyacceptable salt thereof of claim 1 to a host in need thereof.
 37. Themethod of claim 36, wherein the host is a human.
 38. The method of claim37, wherein the disorder is selected from glaucoma, age-related maculardegeneration (AMD), a disorder related to an increase in intraocularpressure (IOP), a disorder related to neuroprotection, or diabeticretinopathy.
 39. The method of claim 37, wherein the disorder is opticnerve damage caused by high intraocular pressure (IOP).
 40. The methodof claim 36, wherein the compound is adminsterined via intravitreal,intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar,peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival,subconjunctival, episcleral, posterior juxtascleral, circumcorneal, ortear duct injection.
 41. The method of claim 36, wherein the compound isadministered via intravitreal injection.
 42. A method for the treatmentof an ocular disorder treatable with both a tyrosine kinase inhibitorand a carbonic anhydrase inhibitor comprising administering atherapeutically effective amount of a compound or pharmaceuticallyacceptable salt thereof of claim 30 to a host in need thereof.
 43. Themethod of claim 42, wherein the host is a human.
 44. The method of claim43, wherein the disorder is selected from glaucoma, age-related maculardegeneration (AMD), a disorder related to an increase in intraocularpressure (IOP), a disorder related to neuroprotection, or diabeticretinopathy.
 45. The method of claim 43, wherein the disorder is opticnerve damage caused by high intraocular pressure (IOP).
 46. The methodof claim 42, wherein the compound is adminsterined via intravitreal,intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar,peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival,subconjunctival, episcleral, posterior juxtascleral, circumcorneal, ortear duct injection.
 47. The method of claim 42, wherein the compound isadministered via intravitreal injection.